bluuebunny/crossref_metadata_2025_split huggingface dataset:
CENP-F controls force generation and the dynein-dependent stripping of CENP-E at kinetochores
Authors: Auckland Philip , McAinsh Andrew D. 
Published: May 2019

AbstractAccurate chromosome segregation demands efficient capture of microtubules by kinetochores and their conversion to stable bi-oriented attachments that can congress and then segregate chromosomes. An early event is the shedding of the outermost fibrous corona layer of the kinetochore following microtubule attachment. Centromere protein F (CENP-F) is part of the corona, contains two microtubule-binding domains and physically associates with dynein motor regulators. Here, we have combined CRISPR gene editing and engineered separation-of-function mutants to define how CENP-F contributes to kinetochore function. We show here that the two microtubule-binding domains make distinct contributions to attachment stability and force generation that are required to minimise errors in anaphase, but are dispensable for congression. We further identify a specialised domain that functions to inhibit the dynein mediated stripping of CENP-E motors. We show how this “dynein-brake” is crucial for ensuring kinetochores contain the right number of CENP-E motors at the right time during mitosis, with loss of brake function delaying congression.
Individual vulnerability to stress is associated with increased demand for intravenous heroin self-administration in rats
Authors: Stafford Nathaniel P. , Kazan Theodore N. , Donovan Colleen M. , Hart Erin E. , Drugan Robert C. , Charntikov Sergios 
Published: May 2019

AbstractOpioid use is a widespread epidemic, and traumatic stress exposure is a critical risk factor in opioid use and relapse. There is a significant gap in our understanding of how stress contributes to heroin use, and there are limited studies investigating individual differences underlying stress reactivity and subsequent stress-induced heroin self-administration. We hypothesized that greater individual vulnerability to stress would predict higher demand for heroin self-administration in a within-subjects rodent model of stress and heroin use comorbidity. Male rats were exposed to inescapable intermittent swim stress and individual biological (corticosterone) or behavioral (open field, social exploration, and forced swim tests) measures were assessed before and after the stress episode. Individual demand for self-administered heroin (0.05 mg/kg/infusion; 12-hour sessions) was assessed using a behavioral economics approach followed by extinction and reinstatement tests triggered by stress re-exposure, non-contingent cue presentations, and yohimbine (0, 1.0, or 2.5 mg/kg). We found that behavioral, biological, and a combination of behavioral and biological markers sampled prior and after the stress episode that occurred weeks before the access to heroin selfadministration predicted the magnitude of individual demand for heroin. Non-contingent presentation of cues, that were previously associated with heroin, reinstated heroin seeking in extinction. For the first time, we show that individual biological response to an ecologically relevant stressor in combination with associated behavioral markers can be used to predict subsequent economic demand for heroin.
Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons
Authors: An Disi , Fujiki Ryosuke , Iannitelli Dylan E. , Smerdon John W. , Maity Shuvadeep , Rose Matthew F. , Gelber Alon , Wanaselja Elizabeth K. , Yagudayeva Ilona , Lee Joun Y. , Vogel Christine , Wichterle Hynek , Engle Elizabeth C. , Mazzoni Esteban O. 
Published: May 2019

SummaryIn amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.
Hippocampal theta coordinates memory processing during visual exploration
Authors: Kragel James E. , VanHaerents Stephen , Templer Jessica W. , Schuele Stephan , Rosenow Joshua M. , Nilakantan Aneesha S. , Bridge Donna J. 
Published: May 2019

SummaryThe hippocampus supports memory encoding and retrieval, with distinct phases of theta oscillations modulating the amplitude of gamma-band activity during each process. Encoding and retrieval operations dynamically interact over rapid timescales, especially when sensory information conflicts with memory. The ability to link hippocampal dynamics to specific memory-guided behaviors has been limited by experiments that lack the temporal resolution to segregate when encoding and retrieval occur. To resolve this issue, we simultaneously tracked eye movements and hippocampal field potentials while neurosurgical patients performed a spatial memory task. Novelty-driven fixations increased phase-locking to the theta rhythm, which predicted successful memory performance. Theta to gamma phase amplitude coupling increased during these viewing behaviors and predicted forgetting of conflicting memories. In contrast, theta phase-locking preceded fixations initiated by memory retrieval, indicating that the hippocampus coordinates memory-guided eye movements. These findings suggest that theta oscillations in the hippocampus support learning through two interleaved processes: strengthening the encoding of novel information and guiding exploration based on prior experience.
Synthetic peptide-induced internalization of biomolecules into various plant and algal cells via micropinocytosis
Authors: Chuah Jo-Ann , Odahara Masaki , Kodama Yutaka , Miyamoto Takaaki , Tsuchiya Kousuke , Motoda Yoko , Kigawa Takanori , Numata Keiji 
Published: May 2019

SummaryEfficient intracellular delivery of biomolecules is important for many different biological and biotechnological applications in living organisms, and is a prerequisite for certain types of fundamental and applied research. One major challenge is the delivery of unmodified, functional cargoes in a simple, time-efficient, and high-throughput manner. Herein, we present an efficient strategy that uses fusion peptides containing cell penetrating peptide, endosomal escape domain, and a sarcosine linker to introduce biomolecules, namely fluorescent protein and dextran, via macropinocytosis into the cells of various land plants and microalgae. Our peptide-mediated delivery system allows for high-throughput delivery of functional biomolecules within a few minutes to a few hours as well as open new possibilities for biology and biotechnology using difficult-to-transfect cell types.
Transcranial alternating current stimulation attenuates BOLD adaptation and increases functional connectivity
Authors: Kar Kohitij , Ito Takuya , Cole Michael , Krekelberg Bart 
Published: May 2019

Transcranial alternating current stimulation (tACS) is used as a non-invasive tool for cognitive enhancement and clinical applications. The physiological effects of tACS, however, are complex and poorly understood (Liu et al. 2018). Most studies of tACS focus on its ability to entrain brain oscillations (Herrmann et al. 2013), but our behavioral results in humans (Kar and Krekelberg 2014a) and extracellular recordings in nonhuman primates (Kar et al. 2017) support the view that tACS at 10 Hz additionally affects brain function by reducing sensory adaptation. Our primary goal here was to test this hypothesis using BOLD imaging in human subjects. Using a motion adaptation paradigm developed to quantify BOLD adaptation (Huk et al. 2001) and concurrent fMRI and tACS, we found that tACS significantly attenuated adaptation in the human motion area (hMT+). In addition, an exploratory analysis showed that tACS increased functional connectivity between the stimulated hMT+ and the rest of the brain, in particular the dorsal attention network. We conclude that weak 10 Hz currents applied to the scalp affect both local and global measures of brain activity.New and NoteworthyConcurrent transcranial alternating current stimulation (tACS) and fMRI show that tACS affects the human brain by attenuating adaptation and increasing functional connectivity. This work is important for our basic understanding of what tACS does, but also for therapeutic applications, which need insight into the full range of ways in which tACS affects the brain.
The plastidial exporter Enhanced Disease Susceptibility 5 is required for the biosynthesis ofN-hydroxy pipecolic acid
Authors: Rekhter Dmitrij , Mohnike Lennart , Feussner Kirstin , Zienkiewicz Krzysztof , Zhang Yuelin , Feussner Ivo 
Published: May 2019

AbstractPipecolic acid is essential for the establishment of systemic acquired resistance in plants. It is synthesized in the plastid and further processed in the cytosol to its active form N-hydroxy pipecolic acid. Here we provide strong evidence that the exporter Enhanced Disease Susceptibility 5 is required for the biosynthesis of not only salicylic acid, but also N-hydroxy pipecolic acid, suggesting that it represents a convergent point of plant immunity.
Computational staining of pathology images to study tumor microenvironment in lung cancer
Authors: Wang Shidan , Rong Ruichen , Yang Donghan M. , Cai Ling , Yang Lin , Luo Danni , Yao Bo , Xu Lin , Wang Tao , Zhan Xiaowei , Xie Yang , Gazdar Adi , Minna John , Xiao Guanghua 
Published: May 2019

ABSTRACTThe spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). In order to facilitate the study of cellular spatial organization and interactions, we developed a comprehensive nuclei segmentation and classification tool to characterize the TME from standard Hematoxylin and Eosin (H&E)-stained pathology images. This tool can computationally “stain” different types of cell nuclei in H&E pathology images to facilitate pathologists in analyzing the TME.A Mask Regional-Convolutional Neural Network (Mask-RCNN) model was developed to segment the nuclei of tumor, stromal, lymphocyte, macrophage, karyorrhexis and red blood cells in lung adenocarcinoma (ADC). Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas (TCGA) lung ADC dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (pv= 0.001), with a hazard ratio of 2.23 [1.37-3.65] after adjusting for clinical variables. Furthermore, the image-derived TME features were significantly correlated with the gene expression of biological pathways. For example, transcription activation of both the T-cell receptor (TCR) and Programmed cell death protein 1 (PD1) pathways was positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway was positively correlated with the density of stromal cells.This study developed a deep learning-based analysis tool to dissect the TME from tumor tissue images. Using this tool, we demonstrated that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways. Although developed from the pathology images of lung ADC, this model can be adapted into other types of cancers.
A domain-resolution map ofin vivoDNA binding reveals the regulatory consequences of somatic mutations in zinc finger transcription factors
Authors: Dogan Berat , Kailasam Senthilkumar , Corchado Aldo Hernández , Nikpoor Naghmeh , Najafabadi Hamed S. 
Published: May 2019

ABSTRACTMulti-zinc finger proteins constitute the largest class of human transcription factors. Their DNA-binding specificity is usually encoded by a subset of their tandem Cys2His2 zinc finger (ZF) domains – the subset that binds to DNA, however, is often unknown. Here, by combining a context-aware machine-learning-based model of DNA recognition within vivobinding data, we characterize the sequence preferences and the ZF subset that is responsible for DNA binding in 209 human multi-ZF proteins. We show thatin vivoDNA binding is primarily driven by ∼50% of the ZFs – these DNA-binding ZFs are under strong selective pressure within and across species, and their mutations affect the expression of hundreds of genes as revealed by pan-cancer trans-eQTL analysis across 18 tissues. Among the genes affected by mutations in multi-ZF proteins, we identify several oncogenic factors regulated by SP1, and show that SP1 up-regulation in cancer promotes the expression of these genes while mutations in SP1 ZFs lead to their repression. Together, these analyses suggest that mutations in DNA-binding ZFs have distinct and widespread regulatory consequences that contribute to transcriptome remodelling in cancer.
Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity
Authors: Petkevicius Kasparas , Virtue Samuel , Bidault Guillaume , Jenkins Benjamin , Çubuk Cankut , Morgantini Cecilia , Aouadi Myriam , Dopazo Joaquin , Serlie Mireille , Koulman Albert , Vidal-Puig Antonio 
Published: May 2019

AbstractWhite adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs from obese mice and humans exhibit markers of increased de novo phosphatidylcholine (PC) biosynthesis rate. Macrophage-specific knockout of phosphocholine-cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower PC turnover, leading to elevated membrane polyunsaturated fatty acids that negated the pro-inflammatory effects of palmitate. Our results reveal a link between obesity-associated increase in PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.
Expanding the Zebrafish Genetic Code through Site-Specific Introduction of Azido-lysine, Bicyclononyne-lysine, and Diazirine-lysine
Authors: Syed Junetha , Palani Saravanan , Clarke Scott T. , Asad Zainab , Bottrill Andrew R. , Jones Alexandra M.E. , Sampath Karuna , Balasubramanian Mohan K 
Published: May 2019

AbstractSite-specific incorporation of un-natural amino acids (UNAA) is a powerful approach to engineer and understand protein function [1-4]. Site-specific incorporation of UNAAs is achieved through repurposing the amber codon (UAG) as a sense codon for the UNAA, a tRNACUA that base pairs with an UAG codon in the mRNA and an orthogonal amino-acyl tRNA synthetase (aaRS) that charges the tRNACUA with the UNAA [5, 6]. Here, we report expansion of the zebrafish genetic code to incorporate the UNAAs, Azido-lysine (AzK), bicyclononyne-lysine (BCNK), and Diazirine-lysine (AbK) into green fluorescent protein (GFP) and Glutathione-S-transferase (GST). We also present proteomic evidence for UNAA incorporation into GFP. Our work sets the stage for the use of UNAA mutagenesis to investigate and engineer protein function in zebrafish.
The atypical Rho GTPase RhoU interacts with Intersectin-2 to regulate endosomal recycling pathways
Authors: Gubar Olga , Croisé Pauline , Kropyvko Sergii , Gryaznova Tetyana , Toth Petra , Blangy Anne , Vitale Nicolas , Rynditch Alla , Gasman Stéphane , Ory Stéphane 
Published: May 2019

AbstractRho GTPases play a key role in various membrane trafficking processes. RhoU is an atypical small Rho GTPase related to Rac/Cdc42 which possesses unique N- and C-terminal domains that regulate its function and its subcellular localization. RhoU localized at the plasma membrane, on endosomes and in cell adhesion structures where it governs cell signalling, differentiation and migration. However, despite its endomembrane localization, RhoU function in vesicular trafficking has been unexplored. Here, we identified intersectins (ITSNs) as new binding partners for RhoU and showed that the second PxxP motif at the N-terminus of RhoU mediated interactions with SH3 domains of ITSNs. To evaluate the function of RhoU and ITSNs in vesicular trafficking, we used fluorescent transferrin as a cargo for uptake experiments. We showed that silencing of either RhoU or ITSN2, but not ITSN1 increased transferrin accumulation in early endosomes resulting from defect in fast vesicle recycling. Concomitantly, RhoU and ITSN2 colocalized to a subset of Rab4-positive vesicles suggesting that RhoU-ITSN2 interaction may occur on fast recycling endosomes to regulate the fate of vesicular cargos.
Cerebro: Interactive visualization of scRNA-seq data
Authors: Hillje Roman , Pelicci Pier Giuseppe , Luzi Lucilla 
Published: May 2019

AbstractSummaryDespite the growing availability of sophisticated bioinformatic methods for the analysis of single-cell RNA-seq data, few tools exist that allow biologists without bioinformatic expertise to directly visualize and interact with their own data and results. Here, we present Cerebro (cell report browser), a Shiny- and Electron-based standalone desktop application for macOS and Windows, which allows investigation and inspection of pre-processed single-cell transcriptomics data without requiring bioinformatic experience of the user.Through an interactive and intuitive graphical interface, users can i) explore similarities and heterogeneity between samples and cells clusters in 2D or 3D projections such as t-SNE or UMAP, ii) display the expression level of single genes or genes sets of interest, iii) browse tables of most expressed genes and marker genes for each sample and cluster.We provide a simple example to show how Cerebro can be used and which are its capabilities. Through a focus on flexibility and direct access to data and results, we think Cerebro offers a collaborative framework for bioinformaticians and experimental biologists which facilitates effective interaction to shorten the gap between analysis and interpretation of the data.AvailabilityCerebro and example data sets are available at https://github.com/romanhaa/Cerebro. Similarly, the R packages cerebroApp and cerebroPrepare R packages are available at https://github.com/romanhaa/cerebroApp and https://github.com/romanhaa/cerebroPrepare, respectively. All components are released under the MIT License.
Structural equation modeling for hypertension and type 2 diabetes based on multiple SNPs and multiple phenotypes
Authors: Jeon Saebom , Shin Ji-yeon , Yee Jaeyong , Park Taesung , Park Mira 
Published: May 2019

AbstractGenome-wide association studies (GWAS) have been successful in identifying genetic variants associated with complex diseases. However, association analyses between genotypes and phenotypes are not straightforward due to the complex relationships between genetic and environmental factors. Moreover, multiple correlated phenotypes further complicate such analyses.To resolve this complexity, we present an analysis using structural equation modeling (SEM). Unlike current methods that focus only on identifying direct associations between diseases and genetic variants such as single-nucleotide polymorphisms (SNPs), our method introduces the effects of intermediate phenotypes, which are related phenotypes distinct from the target, into the systematic genetic study of diseases. Moreover, we consider multiple diseases simultaneously in a single model. The procedure can be summarized in four steps: 1) selection of informative SNPs, 2) extraction of latent variables from the selected SNPs, 3) investigation of the relationships among intermediate phenotypes and diseases, and 4) construction of an SEM. As a result, a quantitative map can be drawn that simultaneously shows the relationship among multiple SNPs, phenotypes, and diseases.In this study, we considered two correlated diseases, hypertension and type 2 diabetes (T2D), which are known to have a substantial overlap in their disease mechanism and have significant public health implications. As intermediate phenotypes for these diseases, we considered three obesity-related phenotypes—subscapular skin fold thickness, body mass index, and waist circumference—as traits representing subcutaneous adiposity, overall adiposity, and abdominal adiposity, respectively. Using GWAS data collected from the Korea Association Resource (KARE) project, we applied the proposed SEM process. Among 327,872 SNPs, 24 informative SNPs were selected in the first step (p<1.0E-05). Ten latent variables were generated in step 2. After an exploratory analysis, we established a path diagram among phenotypes and diseases in step 3. Finally, in step 4, we produced a quantitative map with paths moving from specific SNPs to hypertension through intermediate phenotypes and T2D. The resulting model had high goodness-of fit measures (χ2= 536.52, NFI=0.997, CFI=0.998).
Paternal kin discrimination by sons in male chimpanzees transitioning to adulthood
Authors: Sandel Aaron A. , Mitani John C. , Langergraber Kevin E. 
Published: May 2019

AbstractAlthough paternal investment explains the evolution of fatherhood from a functional perspective, its evolutionary origins are unclear. Here we investigate whether a building block for paternal investment, father-offspring discrimination, is present in our closest living relatives, chimpanzees. Adolescent and young adult males (12 - 21 years old) maintained proximity and groomed with their fathers more frequently than with other males given how often they associated. This discrimination did not likely increase the short-term inclusive fitness of fathers or sons because the absolute time they spent in proximity or grooming did not exceed the time spent in these activities by other dyads. Almost all grooming was done by sons rather than fathers, suggesting that sons are responsible for observed biases in father-son behavior. Father-offspring discrimination could partly be explained by young males socializing with males who were more likely to be their father based on their age at the time of the young male’s conception. Two other cues of paternity, the other male’s rank at the time of the young male’s infancy and the other male’s association frequency with the young male’s mother during the young male’s infancy/juvenility, failed to predict association-controlled proximity or grooming. Father-son biases persisted even after controlling for characteristics of males that predicted paternity probability, implicating other cues that we did not examine. These results suggest that an important factor for the evolution of highly investing fathers in humans, father-offspring discrimination, may have been present in simpler form in the last common ancestor they shared with chimpanzees.