bluuebunny/crossref_metadata_2025_split huggingface dataset:
Releasing a preprint is associated with more attention and citations for the peer-reviewed article
Authors: Fu Darwin Y. , Hughey Jacob J. 
Published: July 2019

AbstractPreprints in biology are gaining popularity, but release of a preprint still precedes only a fraction of peer-reviewed publications. We examined whether having a preprint on bioRxiv was associated with metrics of the corresponding peer-reviewed article. We assembled a dataset of 74,239 articles, 5,405 of which had a preprint, published in 39 journals. Based on log-linear regression and random-effects meta-analysis, articles with a preprint had a 51% higher Altmetric Attention Score and 37% more citations compared to articles without one. These associations were independent of several other article- and author-level variables (e.g., scientific subfield and last author publication age) and unrelated to journal-level variables such as access model and Impact Factor. This observational study can help researchers and publishers make informed decisions about how to incorporate preprints into their work.
Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity
Authors: Amram Shoshik , Iram Tal , Lazdon Ekaterina , Vassar Robert , Ben-Porath Ittai , Frenkel Dan 
Published: July 2019

ABSTRACTAlterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer’s disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-β (Aβ) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in 5xFAD mice. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble Aβ42 induced astrocyte senescence in young naïve mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.
The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1
Authors: Rodríguez-López María , Gonzalez Suam , Hillson Olivia , Tunnacliffe Edward , Codlin Sandra , Tallada Victor A. , Bähler Jürg , Rallis Charalampos 
Published: July 2019

AbstractTarget of Rapamycin Complex 1 (TORC1) signaling promotes growth and ageing. Inhibition of TORC1 leads to a down-regulation of factors that stimulate protein translation, including RNA polymerase III, which in turn contributes to longevity. TORC1-mediated post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less well understood. Here we screened fission yeast deletion mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Mutants lacking the GATA transcription factor Gaf1 (gaf1Δ) grew normally even in high doses of Torin1. The gaf1Δ mutants shortened the chronological lifespan of non-dividing cells and diminished the lifespan extension triggered by Torin1 treatment. Expression profiling and genome-wide binding experiments showed that, after TORC1 inhibition, Gaf1 directly up-regulated genes for small-molecule metabolic pathways and indirectly repressed genes for protein translation. Surprisingly, Gaf1 bound to, and down-regulated the tRNA genes, so also functions as a transcription factor for genes transcribed by RNA polymerase III. We conclude that Gaf1 controls the transcription of both coding and tRNA genes to inhibit translation and growth downstream of TORC1.
Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein
Authors: Landeck Natalie , Strathearn Katherine E. , Ysselstein Daniel , Buck Kerstin , Dutta Sayan , Banerjee Siddhartha , Lv Zhengjian , Hulleman John D. , Hindupur Jagadish , Lin Li-Kai , Padalkar Sonal , McCabe George P. , Stanciu Lia A. , Lyubchenko Yuri L. , Kirik Deniz , Rochet Jean-Christophess 
Published: July 2019

Abstractα-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson’s disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models as well as their biochemical properties relevant to aSyn pathobiology. We report that mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders.
Gclc deletion in surface-ectoderm tissues induces microphthalmia
Authors: Thompson Brian , Chen Ying , Philippe Julien , Anderson David , Golla Jaya Prakash , Davidson Emily , Apostolopoulos Nicholas , Schey Kevin , Katsanis Nicholas , Orlicky David J. , Thompson David , Vasiliou Vasilis 
Published: July 2019

AbstractGlutamate cysteine ligase catalytic subunit (Gclc) is the catalytic subunit for the glutamate-cysteine ligase (Gcl) enzyme. Gcl catalyzes the rate limiting step in glutathione (GSH) synthesis. Gclc is highly expressed in the developing eye. To define the regulatory role of Gclc in eye development, we developed a novel, Le-Cre transgene-driven, Gclc knockout mouse model. Gclcf/f/Le-CreTg/− mice present with deformation of the retina, cornea, iris, and lens, consistent with a microphthalmia phenotype. Controlling for the microphthalmia phenotype of Gclcwt/wt/Le-CreTg/− mice revealed that Gclcf/f/Le-CreTg/− mice have a more severe microphthalmia phenotype. Thus, the loss of Gclc expression exacerbates the microphthalmia phenotype in Le-Cre mice. Gclcf/f/Le-CreTg/− eyes present with reduced retinal and lens epithelium proliferation and increased lens cell death. Imaging mass spectrometry of ocular tissues revealed changes in the intensity and distribution of several lipid species and proteins in the retina and corneas of Gclcf/f/Le-CreTg/− eyes. Lastly, using splice-blocking morpholinos and CRISPR/Cas9, we created two gclc knockdown zebrafish models, both of which display a microphthalmia phenotype. Combined, the mouse and zebrafish results indicate that, in chordates, Gclc has a conserved role in regulating eye development. In summary, these novel animal models are useful tools for elucidating the mechanisms involved in microphthalmia development.
BRCA1 Mediated Homologous Recombination and S Phase DNA Repair Pathways Restrict LINE-1 Retrotransposition in Human Cells
Authors: Sun Xiaoji , Mita Paolo , Kahler David J. , Li Donghui , Wudzinska Aleksandra , Yun Chi , Bader Joel S. , Fenyö David , Boeke Jef D. 
Published: July 2019

AbstractLong interspersed element-1 (LINE-1 or L1) is the only autonomous retrotransposon active in human cells. L1s DNA makes about 17% of the human genome and retrotransposition of a few active L1 copies has been detected in various tumors, underscoring the potential role of L1 in mediating or increasing genome instability during tumorigenic development. Different host factors have been shown to influence L1 mobility through several mechanisms. However, systematic analyses of host factors affecting L1 retrotransposition are limited. Here, we developed a high-throughput microscopy-based retrotransposition assay and coupled it to a genome-wide siRNA knockdown screen to study the cellular regulators of L1 retrotransposition in human cells. We showed that L1 insertion frequency was stimulated by knockdown of Double-Stranded Break (DSB) repair factors that are active in the S/G2 phase of the cell cycle including Homologous Recombination (HR), Fanconi Anemia (FA) and, to a less extent, microhomology-mediated end-joining (MMEJ) factors. In particular, we show that BRCA1, an E3 ubiquitin ligase with a key role in several DNA repair pathways, plays multiple roles in regulating L1; BRCA1 knockdown directly affects L1 retrotransposition frequency and structure and also plays a role in controlling L1 ORF2 protein translation through L1 mRNA binding. These results suggest the existence of a “battle” between HR factors and L1 retrotransposons, revealing a potential role for L1 in development of tumors characterized by BRCA1 and HR repair deficiencies.
Cyclin B1-Cdk1 binding to MAD1 links nuclear pore disassembly to chromosomal stability
Authors: Jackman Mark , Marcozzi Chiara , Pardo Mercedes , Yu Lu , Tyson Adam L. , Choudhary Jyoti S. , Pines Jonathon 
Published: July 2019

AbstractHow the cell completely reorganises its architecture when it divides is a problem that has fascinated researchers for almost 150 years. We now know that the core regulatory machinery is highly conserved in eukaryotes but how these multiple protein kinases, protein phosphatases, and ubiquitin ligases are coordinated to remodel the cell in a matter of minutes remains a major question. Cyclin B-CDK is the primary kinase that drives mitotic remodelling and here we show that it is targeted to the nuclear pore complex (NPC) by binding an acidic face of the spindle assembly checkpoint protein, MAD1. This localised Cyclin B1-CDK1 activity coordinates NPC disassembly with kinetochore assembly: it is needed for the proper release of MAD1 from the embrace of TPR at the nuclear pore, which enables MAD1 to be recruited to kinetochores before nuclear envelope breakdown, thereby strengthening the spindle assembly checkpoint to maintain genomic stability.
A structural mechanism for phosphorylation-dependent inactivation of the AP2 complex
Authors: Partlow Edward A. , Baker Richard W. , Beacham Gwendolyn M. , Chappie Joshua S. , Leschziner Andres E. , Hollopeter Gunther 
Published: July 2019

AbstractEndocytosis of transmembrane proteins is orchestrated by the AP2 clathrin adaptor complex. AP2 dwells in a closed, inactive state in the cytosol, but adopts an open, active conformation on the plasma membrane. Membrane-activated complexes are also phosphorylated, but the significance of this mark is debated. We recently proposed that NECAP negatively regulates AP2 by binding open and phosphorylated complexes (Beacham et al., 2018). Here, we report high-resolution cryo-EM structures of NECAP bound to phosphorylated AP2. The site of AP2 phosphorylation is directly coordinated by residues of the NECAP PHear domain that are predicted from genetic screens in C. elegans. Using membrane mimetics to generate conformationally open AP2, we find that a second domain of NECAP binds these complexes and cryo-EM reveals both domains of NECAP engaging closed, inactive AP2. Assays in vitro and in vivo confirm these domains cooperate to inactivate AP2. We propose that phosphorylation marks adaptors for inactivation.
Giotto, a toolbox for integrative analysis and visualization of spatial expression data
Authors: Dries Ruben , Zhu Qian , Dong Rui , Linus Eng Chee-Huat , Li Huipeng , Liu Kan , Fu Yuntian , Zhao Tianxiao , Sarkar Arpan , Bao Feng , George Rani E , Pierson Nico , Cai Long , Yuan Guo-Cheng 
Published: July 2019

AbstractThe rapid development of novel spatial transcriptomic and proteomic technologies has provided new opportunities to investigate the interactions between cells and their native microenvironment. However, effective use of such technologies requires the development of innovative computational tools that are easily accessible and intuitive to use. Here we present Giotto, a comprehensive, flexible, robust, and open-source toolbox for spatial transcriptomic and proteomic data analysis and visualization. The data analysis module provides end-to-end analysis by implementing a wide range of algorithms for characterizing cell-type distribution, spatially coherent gene expression patterns, and interactions between each cell and its surrounding neighbors. Furthermore, Giotto can also be used in conjunction with external single-cell RNAseq data to infer the spatial enrichment of cell types from data that do not have single-cell resolution. The data visualization module allows users to interactively visualize the gene expression data, analysis outputs, and additional imaging features, thereby providing a user-friendly workspace to explore multiple modalities of information for biological investigation. These two modules can be used iteratively for refined analysis and hypothesis development. We applied Giotto to a wide range of public datasets encompassing diverse technologies and platforms, thereby demonstrating its general applicability for spatial transcriptomic and proteomic data analysis and visualization.
Insulin potentiates JAK/STAT signaling to broadly inhibit flavivirus replication in insect vectors
Authors: Ahlers Laura R.H. , Trammell Chasity E. , Carrell Grace F. , Mackinnon Sophie , Torrevillas Brandi K. , Chow Clement Y. , Luckhart Shirley , Goodman Alan G. 
Published: July 2019

SUMMARYThe World Health Organization estimates that over half of the world’s population is at risk for vector-borne diseases, such as those caused by arboviral infection. Because many arboviruses are mosquito-borne, investigation of the insect immune response will help identify targets that could reduce the spread of these viruses by the mosquito. In this study, we used a genetic screening approach to identifyinsulin-like receptoras a novel component of the immune response to arboviral infection. We determined that vertebrate insulin reduces West Nile virus (WNV) replication inDrosophila melanogasteras well as WNV, Zika, and dengue virus titers in mosquito cells. Mechanistically, we showed that insulin signaling activates the JAK/STAT, but not RNAi, pathway to control infection. Finally, we validated that insulin priming of adult femaleCulexmosquitoes through a blood meal reduces WNV infection, demonstrating an essential role for insulin signaling in insect antiviral responses to emerging human pathogens.
Parameter-dependent shift from rational to irrational decisions in mice
Authors: Schneider Nathan A. , Ballintyn Benjamin , Katz Donald , Lisman John , Pi Hyun-Jae 
Published: July 2019

AbstractIn the classical view of economic choices, subjects make rational decisions evaluating the costs and benefits of options in order to maximize their overall income. Nonetheless, subjects often fail to reach optimal outcomes. The overt value of an option drives the direction of decisions, but covert factors such as emotion and sunk cost are thought to drive the observed deviations from optimality. Many questions remain to be answered as to 1) which contexts contribute the most to deviation from an optimal solution; and 2) the extent of these effects. In order to tackle these questions, we devised a decision-making task for mice, in which cost and benefit parameters could be independently and flexibly adjusted and for which a tractable optimal solution was known. Comparing mouse behavior with this optimal solution across parameter settings revealed that the factor most strongly contributing to suboptimality was the cost parameter. The quantification of sunk cost, a covert factor implicated in our task design, revealed it as another contributor to suboptimality. In one condition where the large reward option was particularly unattractive and the small reward cost was low, the sunk cost effect and the cost-led suboptimality almost vanished. In this regime and this regime only, mice could be viewed as close to rational. Taken together, our findings support a model whereby parallel neural circuits independently activate and modulate multiple valuation algorithms, and suggest that “rationality” is a task-specific construct even in mice.Significant StatementIrrational factors in economic decision-making often cause significant deviation from optimal outcomes. By devising a flexible economic choice behavior for mice and comparing their behavior with an optimal solution, we investigated overt and covert factors that contributed to suboptimal outcomes and quantified the deviation from optimality. This investigation identified regimes where mice could be viewed as rational or irrational depending upon the parameters in the same task. These findings may provide a platform to investigate biological substrates underlying rational and irrational decision factors.
Phospholamban and sarcolipin share similar transmembrane zipper motifs that control self-association affinity and oligomer stoichiometry
Authors: DesLauriers Nicholas R. , Svensson Bengt , Thomas David D. , Autry Joseph M. 
Published: July 2019

AbstractWe have characterized the structural determinants of phospholamban (PLB) and sarcolipin (SLN) self-association using site-directed mutagenesis, SDS-PAGE, and fluorescence resonance energy transfer (FRET) microscopy. PLB and SLN are single-pass transmembrane (TM) peptides that are critically involved in regulation of contractility in cardiac and skeletal muscle via reversible inhibition of calcium (Ca) transport by SERCA. PLB and SLN also exhibit ion channel activityin vitro, yet the physiological significance of these functions is unknown. Here we have determined that structural insights offered by the tetrameric PLB Cys41 to Leu (C41L) mutation, a mutant with four possible leucine/isoleucine zipper interactions for stabilizing PLB tetramers. Using scanning alanine mutagenesis and SDS-PAGE, we have determined the C41L-PLB tetramer is destabilized by mutation of Leu37 to Ala (L37A) or Ile40 to Ala (I40A), which are the samea- andd-arm residues stabilizing the PLB pentamer via leucine/isoleucine zippers, highlighting the importance of these two zippers in PLB higher-order oligomerization. The new possible zipper arm in C41L-PLB (N34, C41L, I48) did not contribute to tetramerization. On the other hand, we determined that tetramer conversion back to pentamer was induced by alanine mutation of Ile48, a residue located on thee-arm below C41L, implicating steric interaction and restriction are the stabilizing and destabilizing forces that control the distribution between pentamer and tetramer populations. We propose that thee-arm and hydrophobic residues in the adjacentb-arm act as secondary structural motifs that help control the stoichiometry of PLB oligomerization. FRET microscopy and alanine mutagenesis of SLN residues Val14 (V14A) or Leu21 (L21A) decreased the binding affinity of the SLN‒SLN complex, demonstrating the importance of each residue in mediating self-association. Helical wheel analysis supports a heptad-repeat TM zipper mechanism of SLN oligomerization, similar to the 3.5 residue/turn Leu and Ile zippers found in PLB pentamers. Collectively, our studies add new insights on the conservation of homologous hydrophobic 3-4 pattern of residues in zipper motifs that mediate PLB and SLN self-assembly. We propose that the importance of these apolar, steric interactions in the TM domain are widespread in stabilizing higher-order oligomerization of membrane proteins.
A missense mutation dissociates triglyceride and phospholipid transfer activities in zebrafish and human microsomal triglyceride transfer protein
Authors: Wilson Meredith H. , Rajan Sujith , Danoff Aidan , White Richard J. , Hensley Monica R. , Quinlivan Vanessa H. , Thierer James H. , Busch-Nentwich Elisabeth M. , Hussain M. Mahmood , Farber Steven A. 
Published: July 2019

SUMMARYMicrosomal triglyceride transfer protein (MTP) transfers triglycerides and phospholipids and is essential for the assembly of Apolipoprotein B (ApoB)-containing lipoproteins in the endoplasmic reticulum. We have discovered a zebrafish mutant (mttpc655) expressing a C-terminal missense mutation (G863V) in Mttp, one of the two subunits of MTP, that is defective at transferring triglycerides, but retains phospholipid transfer activity. Mutagenesis of the conserved glycine in the human MTTP protein (G865V) also eliminates triglyceride but not phospholipid transfer activity. The G863V mutation reduces the production and size of ApoB-containing lipoproteins in zebrafish embryos and results in the accumulation of cytoplasmic lipid droplets in the yolk syncytial layer. However,mttpc655mutants exhibit only mild intestinal lipid malabsorption and normal growth as adults. In contrast, zebrafish mutants bearing the previously identifiedmttpstlmutation (L475P) are deficient in transferring both triglycerides and phospholipids and exhibit gross intestinal lipid accumulation and defective growth. Thus, the G863V point mutation provides the first evidence that the triglyceride and phospholipid transfer functions of a vertebrate MTP protein can be separated, arguing that selective inhibition of the triglyceride transfer activity of MTP may be a feasible therapeutic approach for dyslipidemia.
Regional heterogeneity of developing GABAergic interneuron excitation in vivo
Authors: Murata Yasunobu , Colonnese Matthew T. 
Published: July 2019

AbstractGABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA. By locally manipulating interneuron activity in unanesthetized neonatal mice, we show that GABAergic neurons are indeed excitatory in hippocampus at postnatal-day 3 (P3), and responsible for most of the spontaneous firing of pyramidal cells at that age. Hippocampal interneurons become inhibitory by P7, whereas cortical interneurons are inhibitory at P3 and remain so throughout development. This regional and age heterogeneity is the result of a change in chloride reversal potential as activation of light-gated anion channels expressed in glutamatergic neurons causes firing in hippocampus at P3, but silences it at P7. This study in the intact brain reveals a critical role for GABAergic interneuron excitation in neonatal hippocampus, and a surprising heterogeneity of interneuron function in cortical circuits that was not predicted from in vitro studies.