bluuebunny/crossref_metadata_2025_split huggingface dataset:
Periodicity Scoring of Time Series Encodes Dynamical Behavior of the Tumor Suppressor p53
Authors: Moosmüller Caroline , Tralie Christopher J. , Kooshkbaghi Mahdi , Belkhatir Zehor , Pouryahya Maryam , Reyes José , Deasy Joseph O. , Tannenbaum Allen R. , Kevrekidis Ioannis G. 
Published: February 2020

AbstractIn this paper, we analyze the dynamical behavior of the tumor suppressor protein p53, an essential player in the cellular stress response, which prevents a cell from dividing if severe DNA damage is present. When this response system is malfunctioning, e.g. due to mutations in p53, uncontrolled cell proliferation may lead to the development of cancer. Understanding the behavior of p53 is thus crucial to prevent its failing. It has been shown in various experiments that periodicity of the p53 signal is one of the main descriptors of its dynamics, and that its pulsing behavior (regular vs. spontaneous) indicates the level and type of cellular stress. In the present work, we introduce an algorithm to score the local periodicity of a given time series (such as the p53 signal), which we callDetrended Autocorrelation Periodicity Scoring(DAPS). It applies pitch detection (via autocorrelation) on sliding windows of the entire time series to describe the overall periodicity by a distribution of localized pitch scores. We apply DAPS to the p53 time series obtained from single cell experiments and establish a correlation between the periodicity scoring of a cell’s p53 signal and the number of cell division events. In particular, we show that high periodicity scoring of p53 is correlated to a low number of cell divisions and vice versa. We show similar results with a more computationally intensive state-of-the-art periodicity scoring algorithm based on topology known as Sw1PerS. This correlation has two major implications: It demonstrates that periodicity scoring of the p53 signal is a good descriptor for cellular stress, and it connects the high variability of p53 periodicity observed in cell populations to the variability in the number of cell division events.AMS subject classification92C42, 92C37, 62M10
Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain
Authors: Zhong Jixing , Tang Gen , Zhu Jiacheng , Qiu Xin , Wu Weiying , Li Ge , Lin Xiumei , Liang Langchao , Chai Chaochao , Zeng Yuying , Wang Feiyue , Luo Lihua , Li Jiankang , Chen Fang , Huang Zhen , Xu Xun , Tang Shengping , Zhu Shida , Chen Dongsheng 
Published: February 2020

AbstractParkinson’s disease (PD) is a neurodegenerative disease leading to the impairment of execution of movement. PD pathogenesis has been largely investigated, but either restricted in bulk level or at certain cell types, which failed to capture cellular heterogeneity and intrinsic interplays among distinct cell types. To overcome this, we applied single-nucleus RNA-seq and single cell ATAC-seq on cerebellum, midbrain and striatum of PD mouse and matched control. With 74,493 cells in total, we comprehensively depicted the dysfunctions under PD pathology covering proteostasis, neuroinflammation, calcium homeostasis and extracellular neurotransmitter homeostasis. Besides, by multi-omics approach, we identified putative biomarkers for early stage of PD, based on the relationships between transcriptomic and epigenetic profiles. We located certain cell types that primarily contribute to PD early pathology, narrowing the gap between genotypes and phenotypes. Taken together, our study provides a valuable resource to dissect the molecular mechanism of PD pathogenesis at single cell level, which could facilitate the development of novel methods regarding diagnosis, monitoring and practical therapies against PD at early stage.
Immunological role of primary cilia of dendritic cells in human skin disease
Authors: Toriyama Manami , Rizaldy Defri , Nakamura Motoki , Fujita Fumitaka , Okada Fumihiro , Morita Akimichi , Ishii Ken J. 
Published: February 2020

AbstractPrimary cilia are a unique organelle, known to provide a signaling hub for variety of cell activities. Their potential role(s) in human immune homeostasis and diseases, however, have yet to be explored. Here, we show that human dendritic cells (DCs) express primary cilia-like structure. The primary cilia growth during DC proliferation by GM-CSF was shut off by DC maturation agents, suggesting the role of primary cilia to transduce proliferation signaling. PDGFRα pathway, one of proliferation signal in primary cilia, promoted DC proliferation in a dependent manner of intra-flagellar transport system. In epidermis with atopic dermatitis patients, aberrant ciliated langerhans cells and keratinocytes with showing immature state were observed that may play a potential role in inflammation and skin barrier disorder.
A common problem in the purification of calicivirus raised by molecular sieving: balance between purification and loss of viral particles
Authors: Qu Zehui , Kang Hongtao , Cui Chenxi , Meng Kaiwen , Zhang Xinzheng , Qu Liandong , Meng Geng 
Published: February 2020

AbstractCaliciviridae is a group of RNA viruses could lead to gastrointestinal disease in humans and acute oral or upper respiratory tract disease in felines, no efficient vaccine so far. The preparation of immunogen is a challenge to obtain a safe and efficient vaccine candidate. Molecular sieving, due to the advantage of simple and fast purifying, is considered as a very powerful tool in calicivirus purification; however, also introduce mechanical damage to the viron. In this study, we took Feline Calicivirus (FCV), a common natural pathogen in cats as well as a classic model for caliciviruses studies, as a research object. Here, with the help of the cryo-electron microscope (cryo-EM), we collected particle images in both conditions of with and without molecular sieving post-processing, the impact of molecular sieving on FCV particles was evaluated by building a flexibility evaluation system after 3D classification. The results indicated that the molecular sieving will impact the stability of P domains through increasing flexibility. In addition, we successfully built up a scoring system to describe this flexibility of FCV P-domains, which can be extended to assess the purification effect to the entire calicivirus.
Nanobody-directed targeting of optogenetic tools to study signaling in the primary cilium
Authors: Hansen Jan N. , Kaiser Fabian , Klausen Christina , Stüven Birthe , Chong Raymond , Bönigk Wolfgang , Mick David U. , Möglich Andreas , Jurisch-Yaksi Nathalie , Schmidt Florian I. , Wachten Dagmar 
Published: February 2020

SummaryCompartmentalization of cellular signaling forms the molecular basis of cellular behavior. The primary cilium constitutes a subcellular compartment that orchestrates signal transduction independent from the cell body. Ciliary dysfunction causes severe diseases, termed ciliopathies. Analyzing ciliary signaling and function has been challenging due to the lack of tools to temporarily manipulate and analyze ciliary signaling. Here, we describe a nanobodybased targeting approach for optogenetic tools that is applicablein vitroandin vivoand allows to specifically analyze ciliary signaling and function. Thereby, we overcome the loss of protein function observed after direct fusion to a ciliary targeting sequence. We functionally localized modifiers of cAMP signaling, i.e. the photo-activated adenylate cyclase bPAC and the light-activated phosphodiesterase LAPD, as well as the cAMP biosensor mlCNBD-FRET to the cilium. Using this approach, we studied the contribution of spatial cAMP signaling in controlling cilia length. Combining optogenetics with nanobody-based targeting will pave the way to the molecular understanding of ciliary function in health and disease.
Sexually divergent effects of social dominance on chronic stress outcomes in mice
Authors: Karamihalev Stoyo , Brivio Elena , Flachskamm Cornelia , Stoffel Rainer , Schmidt Mathias V. , Chen Alon 
Published: February 2020

AbstractBackgroundSex and social context are two major factors in the development of depression and other stress-related disorders. However, few studies of the effects of stress on rodent behavior and physiology have investigated social context and fewer still have assessed the possibility of sex-specific effects of social context.MethodsWe assessed social dominance of group-living mice during several days of monitoring using a high-throughput automated behavioral tracking system. We then exposed groups from each sex to a three-week chronic mild stress (CMS) procedure, followed by a behavioral test battery. Finally, we used principle component analysis and post-hoc tests to explore the sources of variance in the behavioral outcome data.ResultsWe found stable hierarchies in both sexes, however social dominance in males exhibited several additional associations with behaviors related to locomotion and exploration that were not seen in females. Crucially, pre-stress social dominance status was associated with opposing outcomes on multiple behavioral readouts between the two sexes following CMS. In particular, subordinate male mice and dominant female mice appeared more responsive to the environmental challenge, as observed in anxiety-like and locomotor behaviors.ConclusionsThis work demonstrates that sex differences interact with preexisting social dominance status to alter the effects of chronic stress. It highlights the importance of understanding the interplay between sex and social context and its contribution to individual differences in stress response.
Current achievements and future developments of a novel AI based visual monitoring of beehives in ecotoxicology and for the monitoring of landscape structures
Authors: Tausch Frederic , Schmidt Katharina , Diehl Matthias 
Published: February 2020

Abstract in EnglishHoney bees are valuable bio-indicators. As such, they hold a vast potential to help shed light on the extent and interdependencies of factors influencing the decline in the number of insects. However, to date this potential has not yet been fully leveraged, as the production of reliable data requires large-scale study designs, which are very labour intensive and therefore costly.A novel Artificial Intelligence (AI) based visual monitoring system could enable the partial automatization of data collection on activity, forager loss and impairment of the central nervous system. The possibility to extract features from image data could prospectively also allow an assessment of pollen intake and a differentiation of dead bees, drones and worker bees as well as other insects such as wasps or hornets.The technology was validated in different studies with regards to its scalability and its ability to extract motion and feature related information.The prospective possibilities were analyzed regarding their potential to enable advances both within ecotoxicological research and the monitoring of pollinator habitats.
The march of the Common Green Iguana (Iguana iguana): early establishment in Singapore and Thailand is facilitated by the pet trade and recreational parks
Authors: van den Burg Matthijs P. , Van Belleghem Steven M. , De Jesús Villanueva Christina N. 
Published: February 2020

AbstractThe popularity of the Common Green Iguana (Iguana iguana) as a pet has contributed to its global occurrence as an invasive alien species. Early detection and control of invasive alienI. iguanapopulations is necessary to prevent the need for large and financially demanding eradication actions. Here, we collated information from digital footage and interviews regarding sightings of free roamingI. iguanaspecimens in Singapore and Thailand, and present evidence of early-stage invasions and establishment. Using species distribution modeling, we find that large parts of Thailand and neighboring countries have suitable habitat, which could facilitate the expansion of these alien populations if left uncontrolled. Additionally, we report singularI. iguanasightings in Hong Kong and Peninsular Malaysia. We call for awareness of alienI. iguanain the Philippines due to the high number of pet iguanas and reported CITES importations as well as the availability of suitable habitat throughout the archipelago. Further, we identifyI. iguanapresence to be facilitated by the release of pet-traded specimens and uncontrolled exhibition practices in recreational parks. We provide recommendations for implementing monitoring and eradication efforts and strategy recommendations to halt future spread and release.
Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma
Authors: Gupta Kshama , Vuckovic Ivan , Zhang Song , Xiong Yuning , Carlson Brett L. , Jacobs Joshua , Olson Ian , Petterson Xuan-Mai , Macura Slobodan I. , Sarkaria Jann , Burns Terry C. 
Published: February 2020

AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.
Human Naïve Epiblast Cells Possess Unrestricted Lineage Potential
Authors: Guo Ge , Stirparo Giuliano Giuseppe , Strawbridge Stanley , Spindlow Daniel , Yang Jian , Clarke James , Dattani Anish , Yanagida Ayaka , Li Meng Amy , Myers Sam , Özel Buse Nurten , Nichols Jennifer , Smith Austin 
Published: February 2020

SUMMARYClassical mouse embryology has established a paradigm of early development driven by sequential lineage bifurcations. Accordingly, mouse embryonic stem cells derived from early epiblast have lost the potency to produce extraembryonic trophectoderm. We show in contrast that human naïve epiblast cells readily make trophectoderm. Inhibition of ERK signalling, instrumental in naïve stem cell propagation, unexpectedly potentiates trophectoderm formation, an effect enhanced by Nodal inhibition. Transcriptome analyses authenticate conversion into trophectoderm with subsequent production of syncitiotrophoblast, cytotrophoblast and trophoblast stem cells. Genetic perturbations indicate that NANOG suppresses and TFAP2C enables trophectoderm induction. Consistent with post-implantation progression, trophectoderm potential is extinguished in conventional human pluripotent stem cells, which instead make amnion. Finally, human embryo epiblasts from late blastocysts efficiently generate trophectoderm and differentiated trophoblast. Thus, pluripotent cells in the human embryo retain extraembryonic lineage plasticity and regenerative potential until implantation. Harnessing this unanticipated regulative capacity may be beneficial for assisted reproduction technology.
Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis
Authors: van Zyl Tavé , Yan Wenjun , McAdams Alexi , Peng Yi-Rong , Shekhar Karthik , Regev Aviv , Juric Dejan , Sanes Joshua R. 
Published: February 2020

ABSTRACTIncreased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells that carry information from the eye to the brain; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye, called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single cell RNA sequencing (scRNA-seq). From ∼24,000 single cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa) and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma, and for using model systems to assess mechanisms and potential interventions.
SNF1-related protein kinase 2 directly regulate group C Raf-like protein kinases in abscisic acid signaling
Authors: Kamiyama Yoshiaki , Hirotani Misaki , Ishikawa Shinnosuke , Minegishi Fuko , Katagiri Sotaro , Takahashi Fuminori , Nomoto Mika , Ishikawa Kazuya , Kodama Yutaka , Tada Yasuomi , Takezawa Daisuke , Peck Scott C. , Shinozaki Kazuo , Umezawa Taishi 
Published: February 2020

ABSTRUCTA phytohormone abscisic acid (ABA) has a major role in abiotic stress responses in plants, and subclass III SNF1-related protein kinase 2 (SnRK2) mediates ABA signaling. In this study, we identified Raf36, a group C Raf-like protein kinase in Arabidopsis, as an interacting protein with SnRK2. A series of reverse genetic and biochemical analyses revealed that Raf36 negatively regulates ABA responses and is directly phosphorylated by SnRK2s. In addition, we found that Raf22, another C-type Raf-like kinase, functions partially redundantly with Raf36 to regulate ABA responses. Comparative phosphoproteomic analysis using Arabidopsis wild-type andraf22raf36-1plants identified proteins that are phosphorylated downstream of Raf36 and Raf22in planta. Together, these results reveal a novel subsection of ABA-responsive phosphosignaling pathways branching from SnRK2.
A designer FG-Nup that reconstitutes the selective transport barrier of the Nuclear Pore Complex
Authors: Fragasso Alessio , de Vries Hendrik W. , van der Sluis Eli O. , van der Giessen Erik , Onck Patrick R. , Dekker Cees 
Published: February 2020

AbstractNuclear Pore Complexes (NPCs) regulate bidirectional transport between the nucleus and the cytoplasm. Intrinsically disordered FG-Nups line the NPC lumen and form a selective barrier, where transport of most proteins is inhibited whereas specific transporter proteins freely pass. The mechanism underlying selective transport through the NPC is still debated. Here, we reconstitute the selective behaviour of the NPC bottom-up by introducing a rationally designed artificial FG-Nup that mimics natural Nups. Using QCM-D, we measure a strong affinity of the artificial FG-Nup brushes to the transport receptor Kap95, whereas no binding occurs to cytosolic proteins such as BSA. Solid-state nanopores with the artificial FG-Nups lining their inner walls support fast translocation of Kap95 while blocking BSA, thus demonstrating selectivity. Coarse-grained molecular dynamics simulations highlight the formation of a selective meshwork with densities comparable to native NPCs. Our findings show that simple design rules can recapitulate the selective behaviour of native FG-Nups and demonstrate that no specific spacer sequence nor a spatial segregation of different FG-motif types are needed to create functional NPCs.
Examination of the efficacy of small genetic panels in genomic conservation of companion animal populations
Authors: Sams Aaron J. , Ford Brett , Gardner Adam , Boyko Adam R. 
Published: February 2020

ABSTRACTIn many ways dogs are an ideal model for the study of genetic erosion and population recovery, problems of major concern in the field of conservation genetics. Genetic diversity in many dog breeds has been declining systematically since the beginning of the 1800’s, when modern breeding practices came into fashion. As such, inbreeding in domestic dog breeds is substantial and widespread and has led to an increase in recessive deleterious mutations of high effect as well as general inbreeding depression. Pedigrees can in theory be used to guide breeding decisions, though are often incomplete and do not reflect the full history of inbreeding. Small microsatellite panels are also used in some cases to choose mating pairs to produce litters with low levels of inbreeding. However, the long-term impact of such practices have not been thoroughly evaluated. Here, we use forward simulation on a model of the dog genome to examine the impact of using limited markers panels to guide pairwise mating decisions on genome-wide population level genetic diversity. Our results suggest that in unsupervised mating schemes, where breeding decisions are made at the pairwise-rather than population-level, such panels can lead to accelerated loss of genetic diversity compared to random mating at regions of the genome unlinked to panel markers and demonstrate the importance of genome-wide genetic panels for managing and conserving genetic diversity in dogs and other companion animals.