bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interplay of synaptic plasticity and scaling enables self-organized formation and allocation of multiple memory representations
Authors: Maria Auth Johannes , Nachstedt Timo , Tetzlaff Christian 
Published: February 2018

ABSTRACTIt is commonly assumed that memories about experienced stimuli are represented by groups of highly interconnected neurons called cell assemblies. This requires allocating and storing information in the neural circuitry, which happens through synaptic weight adaptation. It remains, however, largely unknown how memory allocation and storage can be achieved and coordinated to allow for a faithful representation of multiple memories without disruptive interference between them. In this theoretical study, we show that the interplay between conventional synaptic plasticity and homeostatic synaptic scaling organizes synaptic weight adaptations such that a new stimulus forms a new memory and where different stimuli are assigned to distinct cell assemblies. The resulting dynamics can reproduce experimental in-vivo data, focusing on how diverse factors as neuronal excitability and network connectivity, influence memory formation. Thus, the here presented model suggests that a few fundamental synaptic mechanisms may suffice to implement memory allocation and storage in neural circuitry.
The role of Aβ circRNA in Alzheimer’s disease: alternative mechanism of Aβ biogenesis from Aβ circRNA translation
Authors: Mo Dingding , Li Xinping , Raabe Carsten A. , Rozhdestvensky Timofey S. , Skryabin Boris V. , Brosius Juergen 
Published: February 2018

AbstractAlzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ is generated from the full-length amyloid precursor protein (APP) via dysregulated proteolytic processing. However, Aβ biogenesis in case of sporadic AD remains so far elusive. circRNAs are a class of transcripts, which are preferentially expressed in brain. Here, we identified a circRNA (circAβ-a) derived from the Aβ-coding region of the APP gene. circAβ-a is expressed in brains of AD and nondementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-related Aβ175 protein in living cells. Importantly, Aβ175 was further processed to Aβ peptides, the hallmark of AD. In summary, our analysis revealed alternative route of Aβ biogenesis. circAβ-a and its corresponding protein might represent novel therapeutic targets for AD treatment.
Molecular basis of mitotic decline during human aging
Authors: Macedo Joana Catarina , Vaz Sara , Bakker Bjorn , Ribeiro Rui , Bakker Petra , Escandell Jose Miguel , Ferreira Miguel Godinho , Medema René , Foijer Floris , Logarinho Elsa 
Published: February 2018

AbstractAneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome segregation defects in elderly mitotic cells correlated with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives expression of most G2/M genes. By restoring FoxM1 levels in elderly and Hutchison-Gilford Progeria Syndrome fibroblasts we prevented aneuploidy and, importantly, ameliorated cellular phenotypes associated with aging. Moreover, senescent fibroblasts isolated from elderly donors’ cultures were mostly aneuploid, suggesting that aneuploidy is a key player in the progression into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.
The subesophageal ganglion modulates locust inter-leg sensory-motor interactions via contralateral pathways
Authors: Knebel Daniel , Wörner Johanna , Rillich Jan , Nadler Leonard , Ayali Amir , Couzin-Fuchs Einat 
Published: February 2018

AbstractThe neural control of insect locomotion is distributed among various body segments. Local pattern-generating circuits at the thoracic ganglia interact with incoming sensory signals and central descending commands from the head ganglia. The evidence from different insect preparations suggests that the subesophageal ganglion (SEG) may play an important role in locomotion-related tasks. In a previous study, we demonstrated that the locust SEG modulates the coupling pattern between segmental leg CPGs in the absence of sensory feedback. Here, we investigated its role in processing and transmitting sensory information to the leg motor centers, and mapped the major related neural pathways. Specifically, the intra- and inter-segmental transfer of leg-feedback were studied by simultaneously monitoring motor responses and descending signals from the SEG. Our findings reveal a crucial role of the SEG in the transfer of intersegmental, but not intrasegmental, signals. Additional lesion experiments, in which the intersegmental connectives were cut at different locations, together with double nerve staining, indicated that sensory signals are mainly transferred to the SEG via the connective contralateral to the stimulated leg. We therefore suggest that, similar to data reported for vertebrates, insect leg sensory-motor loops comprise contralateral ascending pathways to the head and ipsilateral descending ones.
Using movement data to estimate contact rates in a simulated environmentally-transmitted disease system
Authors: Dougherty Eric R. , Seidel Dana P. , Carlson Colin J. , Getz Wayne M. 
Published: February 2018

AbstractAgent-based models have become important tools in ecology, particularly in the study of infectious disease dynamics. Simulations of near-continuous movement paths guided by empirical data offer new avenues of investigation into disease transmission. Here, we simulate the spatiotemporal transmission dynamics of anthrax, the acute disease caused by the bacteriumBacillus anthracis, a pathogen transmitted primarily via environmental reservoirs. We explore how calculations of the probabilities of contact between a host and infectious reservoirs are affected by the scale and method of analysis. At both the landscape and individual scales, empirical movement tracks offer previously unattainable estimates of impacts of movement decisions on contact rate metrics. However, the analytical method selected for the calculation of the probability of contact has notable impacts on the resulting estimates, with convex polygons virtually canceling out variation, and unions of local convex hulls (LoCoH methods) and space-time prisms reflecting reasonable variation, but differing in the magnitude of their estimates. The explicit consideration of behavioral states along movement pathways also impacts evaluations of exposure risk, though its effects differ across methods of analysis. Ultimately, simulations demonstrate that the incorporation of movement data into pathogen transmission analyses helps clarify the role of movement processes underlying the observed dynamics of infectious disease.
Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response ELOVL6 modifies ER stress
Authors: Palu Rebecca A. S. , Chow Clement Y. 
Published: February 2018

ABSTRACTEndoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in genes involved in the ER stress response has been linked to inter-individual differences in this response. However, the mechanisms and pathways by which genetic modifiers are acting on the ER stress response remain unclear. In this study, we characterize the role of the long chain fatty acid elongase Baldspot (ELOVL6) in modifying the ER stress response and disease. We demonstrate that loss of Baldspot rescues degeneration and reduces IRE1 and PERK signaling and cell death in a Drosophila model of retinitis pigmentosa and ER stress (Rh1G69D). Dietary supplementation of stearate bypasses the need for Baldspot activity. Finally, we demonstrate that Baldspot regulates the ER stress response across different tissues and induction methods. Our findings suggest that ELOVL6 is a promising target in the treatment of not only retinitis pigmentosa, but a number of different ER stress-related disorders.AUTHOR SUMMARYDifferences in genetic background drives disease variability, even among individuals with identical, causative mutations. Identifying and understanding how genetic variation impacts disease expression could improve diagnosis and treatment of patients. Previous work has linked the endoplasmic reticulum (ER) stress response pathway to disease variability. When misfolded proteins accumulate in the ER, the ER stress response returns the cell to its normal state. Chronic ER stress leads to massive amounts of cell death and tissue degeneration. Limiting tissue loss by regulating the ER stress response has been a major focus of therapeutic development. In this study, we characterize a novel regulator of the ER stress response, the long chain fatty acid elongase Baldspot/ELOVL6. In the absence of this enzyme, cells undergoing ER stress display reduced cell death, and degeneration in a Drosophila disease model. Feeding of excess fatty acids increases degeneration to original disease levels, linking the regulatory activity of Baldspot to its enzymatic activity. Finally, we demonstrate that Baldspot can alter the ER stress response under a variety of other ER stress conditions. Our studies demonstrate that Baldspot/ELOVL6 is a ubiquitous regulator of the ER stress response and is a good candidate therapeutic target.
Inducible expression of immediate early genes is regulated through dynamic chromatin association by NF45/ILF2and NF90/ILF3
Authors: Wu Ting-Hsuan , Shi Lingfang , Lowe Anson W. , Nicolls Mark R. , Kao Peter N. 
Published: February 2018

ABSTRACTImmediate early gene (IEG) transcription is rapidly activated by diverse stimuli without requiring new protein synthesis. This transcriptional regulation is assumed to involve constitutively expressed nuclear factors that are targets of signaling cascades initiated at the cell membrane. NF45 and its heterodimeric partner NF90 are chromatin-interacting proteins that are constitutively expressed and localized predominantly in the nucleus. Previously, NF90 chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in K562 erythroleukemia cells revealed its enriched association with chromatin at active promoters and strong enhancers. NF90 specifically occupied the promoters of IEGs. Here, ChIP in serum-starved HEK293 cells demonstrated that NF45 and NF90 pre-exist and specifically occupy the promoters of IEG transcription factorsEGR1,FOSandJUN. Cellular stimulation with phorbol myristyl acetate increased NF90 occupancy, while decreasing NF45 occupancy at promoters ofEGR1,FOSandJUN. In HEK293 cells stably transfected with doxycycline-inducible shRNA vectors targeting NF90 or NF45, doxycycline-mediated knockdown of NF90 or NF45 attenuated the inducible expression ofEGR1,FOS, andJUNat the levels of mRNA and protein. NF90 and NF45 operate as constitutively-expressed transcriptional regulators of IEGs. Dynamic chromatin association of NF45 and NF90 at IEG promoters are observed upon stimulation, and NF45 and NF90 contribute to inducible expression of IEGs. NF45 and NF90 operate as chromatin regulators of the immediate early response.
Perceptual insensitivity to higher-order statistical moments of coherent random dot motion
Authors: Waskom Michael L. , Asfour Janeen , Kiani Roozbeh 
Published: February 2018

ABSTRACTWhen the visual system analyses distributed patterns of sensory inputs, what features of those distributions does it use? It has been previously demonstrated that higher-order statistical moments of luminance distributions influence perception of static surfaces and textures. Here, we tested whether the brain also represents higher-order moments of dynamic stimuli. We constructed random dot kinematograms where dots moved according to probability distributions that selectively differed in terms of their mean, variance, skewness, or kurtosis. When viewing these stimuli, human observers were sensitive to the mean direction of coherent motion and to the variance of the individual dot displacement angles, but they were insensitive to skewness and kurtosis. Observer behavior accorded with a model of directional motion energy, suggesting that information about higher-order moments is discarded early in the visual processing hierarchy. These results demonstrate that use of higher-order moments is not a general property of visual perception.
A novel surfactant protein is associated with extrapulmonary respiration in lungless salamanders
Authors: Lewis Zachary R. , Dorantes Jorge A. , Hanken James 
Published: February 2018

AbstractNumerous physiological and morphological adaptations were achieved during the transition to lungless respiration following evolutionary lung loss in plethodontid salamanders, including those that enable efficient gas exchange across extrapulmonary tissue. However, the molecular basis of these adaptations is unknown. Here we show that lungless salamanders express in the skin and buccal cavity—the principal sites of respiratory gas exchange in these species—a novel paralog of the gene Surfactant-Associated Protein C (SFTPC), which is a critical component of pulmonary surfactant expressed exclusively in the lung in other vertebrates. The paralogous gene appears to be found only in salamanders, but, similar to SFTPC, in lunged salamanders it is expressed only in the lung. This heterotopic gene expression, combined with predictions from structural modeling and respiratory tissue ultrastructure, suggest that lungless salamanders produce pulmonary surfactant-like secretions outside the lungs and that the novel paralog of SFTPC might facilitate extrapulmonary respiration in the absence of lungs. Heterotopic expression of the SFTPC paralog may have contributed to the remarkable evolutionary radiation of lungless salamanders, which account for more than two thirds of urodele species alive today.
An annual cycle of gene regulation in the red-legged salamander mental gland: from hypertrophy to expression of rapidly evolving pheromones
Authors: Wilburn Damien B. , Feldhoff Richard C. 
Published: February 2018

AbstractCell differentiation is mediated by synchronized waves of coordinated expression for hundreds to thousands of genes, and must be an exquisitely regulated process to produce complex tissues and phenotypes. For many animal species, sexual selection has driven the development of elaborate male ornaments, requiring sex-specific differentiation pathways. One such male ornament is the pheromone-producing mental gland of the red-legged salamander (Plethodon shermani). Mental gland development follows an annual cycle of extreme hypertrophy, production of pheromones for the ~2 month mating season, and then complete resorption before repeating the process in the following year. At the peak of the mating season, the transcriptional and translational machinery of the mental gland are almost exclusively redirected to synthesis of many rapidly evolving pheromones. Of these pheromones, Plethodontid Modulating Factor (PMF) has experienced an unusual history of disjunctive evolution: following gene duplication, positive sexual selection has diversified the protein coding region while the untranslated regions have been conserved by purifying selection. However, the molecular underpinnings that bridge the processes of gland hypertrophy, pheromone synthesis, and disjunctive evolution remain to be determined and are the focus of the present investigation. Using Illumina sequencing, we prepared a de novo transcriptome of the mental gland at six stages of development. Differential expression analysis and immunohistochemistry revealed that the mental gland initially adopts a highly proliferative, almost tumor-like phenotype, followed by a rapid increase in pheromone mRNA and protein levels. One likely player in this transition is Cold Inducible RNA Binding Protein (CIRBP), which selectively and cooperatively binds the highly conserved PMF 3′ UTR. CIRBP, along with other stress response proteins, have seemingly been co-opted to aid in mental gland development by helping to regulate pheromone synthesis. The P. shermani mental gland utilizes a complex system of transcriptional and post-transcriptional gene regulation to facilitate its hypertrophication and pheromone synthesis. The data support the evolutionary interplay of both coding and noncoding segments in rapid gene evolution, and necessitate study of the co-evolution of pheromone gene products along with their transcriptional and translational regulators. Additionally, the mental gland could be a powerful emerging model of regulated proliferation and subsequent resorption of a tissue, within the dermis, thus having potential links to skin cancer biology.
A database of simulated tumor genomes towards accurate detection of somatic small variants in cancer
Authors: Meng Jing , Chen Yi-Ping Phoebe 
Published: February 2018

AbstractBackgroundSomatic mutations promote the transformation of normal cells to cancer. Accurate identification of such mutations facilitates cancer diagnosis and treatment. A number of callers have been developed to predict them from paired tumor/normal or unpaired tumor sequencing data. However, the small size of currently available experimentally validated somatic sites limits evaluation and then improvement of callers. Fortunately, NIST reference material NA12878 genome has been well-characterized with publicly available high-confidence genotype calls.ResultsWe used BAMSurgeon to create simulated tumors by introducing somatic small variants (SNVs and small indels) into homozygous reference or wildtype sites of NA12878. We generated 135 simulated tumors from 5 pre-tumors/normals. These simulated tumors vary in sequencing and subsequent mapping error profiles, read length, the number of sub-clones, the VAF, the mutation frequency across the genome and the genomic context. Furthermore, these pure tumor/normal pairs can be mixed at desired ratios within each pair to simulate sample contamination.ConclusionsThis database (a total size of 15 terabytes) will be of great use to benchmark somatic small variant callers and guide their improvement.Contact informationjing.mengrabbit@gmail.com
Identification and characterization of moonlighting long non-coding RNAs based on RNA and protein interactome
Authors: Cheng Lixin , Leung Kwong-Sak 
Published: February 2018

AbstractMoonlighting proteins are a class of proteins having multiple distinct functions, which play essential roles in a variety of cellular and enzymatic functioning systems. Although there have long been calls for computational algorithms for the identification of moonlighting proteins, research on approaches to identify moonlighting long non-coding RNAs (lncRNAs) has never been undertaken. Here, we introduce a methodology, MoonFinder, for the identification of moonlighting lncRNAs. MoonFinder is a statistical algorithm identifying moonlighting lncRNAs without a priori knowledge through the integration of protein interactome, RNA-protein interactions, and functional annotation of proteins. We identify 155 moonlighting lncRNA candidates and uncover that they are a distinct class of lncRNAs characterized by specific sequence and cellular localization features. The non-coding genes that transcript moonlighting lncRNAs tend to have shorter but more exons and the moonlighting lncRNAs have a localization tendency of residing in the cytoplasmic compartment in comparison with the nuclear compartment. Moreover, moonlighting lncRNAs and moonlighting proteins are rather mutually exclusive in terms of both their direct interactions and interacting partners. Our results also shed light on how the moonlighting candidates and their interacting proteins implicated in the formation and development of cancers and other diseases.
A Single Mechanism of Biogenesis, Initiated and Directed by PIWI Proteins, Explains piRNA Production in Most Animals
Authors: Gainetdinov Ildar , Colpan Cansu , Arif Amena , Cecchini Katharine , Zamore Phillip D. 
Published: February 2018

SummaryIn animals, piRNAs guide PIWI-proteins to silence transposons and regulate gene expression. The mechanisms for making piRNAs have been proposed to differ among cell types, tissues, and animals. Our data instead suggest a single model that explains piRNA production in most animals. piRNAs initiate piRNA production by guiding PIWI proteins to slice precursor transcripts. Next, PIWI proteins direct the stepwise fragmentation of the sliced precursor transcripts, yielding tail-to-head strings of phased pre-piRNAs. Our analyses detect evidence for this piRNA biogenesis strategy across an evolutionarily broad range of animals including humans. Thus, PIWI proteins initiate and sustain piRNA biogenesis by the same mechanism in species whose last common ancestor predates the branching of most animal lineages. The unified model places PIWI-clade Argonautes at the center of piRNA biology and suggests that the ancestral animal—the Urmetazoan—used PIWI proteins both to generate piRNA guides and to execute piRNA function.
Lineage tracing axial progenitors using Nkx1.2CreERT2mice defines their trunk and tail contributions
Authors: Albors Aida Rodrigo , Halley Pamela A. , Storey Kate G. 
Published: February 2018

AbstractThe vertebrate body forms by continuous generation of new tissue from progenitors at the posterior end of the embryo. In mice, these axial progenitors initially reside in the epiblast, from where they form the trunk; and later relocate to the chordo-neural hinge of the tail bud to form the tail. Among them, a small group of bipotent neuromesodermal progenitors (NMPs) are thought to generate the spinal cord and paraxial mesoderm to the end of axis elongation. The study of these progenitors, however, has proven challengingin vivodue to their small numbers and dynamic nature, and the lack of a unique molecular marker to identify them. Here, we report the generation of the Nkx1.2CreERT2transgenic mouse line in which the endogenousNkx1.2promoter drives tamoxifen-inducible CreERT2recombinase. We show that Nkx1.2CreERT2targets axial progenitors, including NMPs and early neural and mesodermal progenitors. Using a YFP reporter, we demonstrate thatNkx1.2-expressing epiblast cells contribute to all three germ layers, mostly neuroectoderm and mesoderm excluding notochord; and continue contributing neural and paraxial mesoderm tissues from the tail bud. This study identifies theNkx1.2-expressing cell population as the source of most trunk and tail tissues in the mouse; and provides a key tool to genetically label and manipulate this progenitor populationin vivo.