bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of two strongly divergent archaellins stabilizes the structure of theHalorubrumarchaellum
Authors: Pyatibratov Mikhail G. , Syutkin Alexey S. , Quax Tessa E.F. , Melnik Tatjana N. , Papke R. Thane , Gogarten Johann Peter , Kireev Igor I. , Surin Alexey K. , Beznosov Sergei N. , Galeva Anna V. , Fedorov Oleg V. 
Published: November 2019

SUMMARYThe archaellum is a unique motility structure that has only functional similarity to its bacterial counterpart, the flagellum. Archaellar filaments consist of thousands of copies of the protein protomer archaellin. Most euryarchaeal genomes encode multiple homologous archaellins. The role of these multiple archaellin genes remains unclear. Halophilic archaea from the genusHalorubrumpossess two archaellin genes,flaB1andflaB2. Amino acid sequences of the corresponding protein products are extraordinarily diverged (identity of ∼ 40%). To clarify roles for each archaellin, we compared archaella from two naturalHalorubrum lacusprofundistrains: the DL18 strain, which possesses both archaellin genes, and the type strain ACAM 34 whose genome contains theflaB2gene only. Both strains synthesize functional archaella; however, the DL18 strain, where both archaellins are present in comparable amounts, is more motile. In addition, we expressed these differentHrr. lacusprofundiarchaellins in aHaloferax volcaniistrain from which the endogenous archaellin genes were deleted. ThreeHfx. volcaniistrains expressingHrr. lacusprofundiarchaellinsflaB1,flaB2orflaB1-flaB2produced archaellum filaments consisting of only one (FlaB1 or FlaB2) or both (FlaB1/B2) archaellins. All three recombinantHfx. volcaniistrains were motile, although there were profound differences in the efficiency of motility. The recombinant filaments resemble the natural filaments ofHrr. lacusprofundi. Electron microscopy showed that FlaB1 FlaB2-archaella look like typical supercoiled filaments, while with the shape of the FlaB1- and FlaB2-archaella is more variable. Both native and recombinant FlaB1 FlaB2-filaments have greater thermal stability and are more resistant to low salinity stress than single-component filaments. This shows that thermal stability of archaellins depends on the presence of both archaellin types, indicating a close interaction between these subunits in the supramolecular structure. Functional helicalHrr. lacusprofundiarchaella can be composed of either single archaellin: FlaB2 or FlaB1; however, the two divergent archaellin subunits in combination provide additional stabilization to the archaellum structure and thus adaptation to a wider range of external conditions. A comparative genomic analysis of archaellins suggests that the described combination of divergent archaellins is not restricted toHrr. lacusprofundi,but is occurring also in organisms from other haloarchaeal genera.
A Systems Approach Identifies Enhancer of Zeste Homolog 2 (EZH2) as a Protective Factor in Epilepsy
Authors: Khan Nadia , Schoenike Barry , Basu Trina , Grabenstatter Heidi , Rodriguez Genesis , Sindic Caleb , Johnson Margaret , Wallace Eli , Maganti Rama , Dingledine Raymond , Roopra Avtar 
Published: November 2019

AbstractComplex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after seizure induction robustly increases spontaneous seizure burden weeks later. Thus, EZH2 upregulation is a protective response mounted after a seizure. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.Author SummaryEpilepsy is the fourth most common neurological disorder and has been described since the time of Hippocrates. Despite this, no treatments exist to stop epilepsy progression. This is fundamentally due to the complex nature of the disease. Epilepsy is associated with hundreds if not thousands of gene expression changes in the brain that are likely driven by a few key master regulators called transcription factors and cofactors. Finding the aberrantly acting factors is a complex problem that currently lacks a satisfactory solution. We used a novel datamining tool to define key master regulators of gene expression changes across multiple epilepsy models and patient samples. We find that a nuclear enzyme, EZH2, regulates a large number of genes in the rodent and patient epileptic brain and that it’s function is protective. Thus, inhibiting EZH2 greatly exacerbates seizure burden. This is the first report of a novel datamining tool to define drivers of large-scale gene changes and is also the first report of EZH2 induction as an endogenous protective response in the epilepsy.
Geometry and evolution of the ecological niche in plant-associated microbes
Authors: Chaloner Thomas M. , Gurr Sarah J. , Bebber Daniel P. 
Published: November 2019

AbstractThe ecological niche of a species can be conceptualized as a volume in multidimensional space, where each dimension describes an abiotic condition or biotic resource. The shape and size of this volume strongly determines interactions among species and influences their global distribution, but the geometry of the niche is poorly understood. Here, we analyse temperature response functions and host plant ranges for hundreds of fungi and oomycetes. We demonstrate that niche specialization is independent on abiotic and biotic axes, that host interactions restrict fundamental niche breadth to form the realized niche, and that both abiotic and biotic niches show limited phylogenetic constraint. Such niche adaptability makes plant pathogens a formidable threat to agriculture and forestry.
Dynamic DNA-based information storage
Authors: Lin Kevin N. , Keung Albert J. , Tuck James M. 
Published: November 2019

AbstractTechnological leaps are often driven by key innovations that transform the underlying architectures of systems. Current DNA storage systems largely rely on polymerase chain reaction, which broadly informs how information is encoded, databases are organized, and files are accessed. Here we show that a hybrid ‘toehold’ DNA structure can unlock a fundamentally different, dynamic DNA-based information storage system architecture with broad advantages. This innovation increases theoretical storage densities and capacities by eliminating non-specific DNA-DNA interactions common in PCR and increasing the encodable sequence space. It also provides a physical handle with which to implement a range of in-storage file operations. Finally, it reads files non-destructively by harnessing the natural role of transcription in accessing information from DNA. This simple but powerful toehold structure lays the foundation for an information storage architecture with versatile capabilities.
Dynamic Genome Evolution and Blueprint of Complex Virocell Metabolism in Globally-Distributed Giant Viruses
Authors: Moniruzzaman Mohammad , Martinez-Gutierrez Carolina A. , Weinheimer Alaina R. , Aylward Frank O. 
Published: November 2019

AbstractThe discovery of giant viruses with large genomes has transformed our understanding of the limits of viral complexity in the biosphere, and subsequent research in model virus-host systems has advanced our knowledge of intricate mechanisms used by these viruses to take over host cells during infection. The extent of the metabolic diversity encoded by these viruses in the environment is less well-understood, however, and their potential impact on global biogeochemical cycles remains unclear. To address this, we generated 501 metagenome-assembled genomes (MAGs) of NCLDVs from diverse environments around the globe and analyzed their encoded functional diversity and potential for reprogramming host physiology. We found that 476 (95%) of the MAGs belonged to the Mimiviridae and Phycodnaviridae families, and of these we recovered 96% from aquatic environments, highlighting the diversity of these viral families in global freshwater and marine systems. MAGs encoded diverse genes predicted to be involved in nutrient uptake and processing, light harvesting, central nitrogen metabolism, and the manipulation of cell death, underscoring the complex interplay between these viruses and their hosts. Surprisingly, numerous genomes encoded genes involved in glycolysis, gluconeogenesis, and the TCA cycle, including one genome with a 70%-complete glycolytic pathway, suggesting that many of these viruses can even reprogram fundamental aspects of their host’s central carbon metabolism. Phylogenetic trees of NCLDV metabolic genes together with their cellular homologs revealed distinct clustering of viral sequences into divergent clades, indicating these metabolic genes are virus-specific and were acquired in the distant past. Our findings reveal that diverse NCLDV genomes encode complex, cell-like metabolic capabilities with evolutionary histories that are largely independent of cellular life, strongly implicating them as distinct drivers of biogeochemical cycles in their own right.
Nightmares share strong genetic risk with sleep and psychiatric disorders
Authors: Ollila Hanna M , Sinnott-Armstrong Nasa , Kantojärvi Katri , Palviainen Teemu , Pandit Anita , Rong Robin , Kristiansson Kati , Sandman Nils , Valli Katja , Hublin Christer , Kaprio Jaakko , Saxena Richa , Paunio Tiina 
Published: November 2019

ABSTRACTNightmares are vivid, extended and extremely dysphoric dreams that awaken the dreamer. Twin studies indicate that nightmare frequency has a heritability between 36 and 51% providing evidence for genetic factors underlying predisposition to nightmares. Furthermore, while cross-sectional epidemiological findings suggest that heavy alcohol usage, traumatic experiences and psychiatric diseases associate with nightmares, the causal relationships between these conditions and nightmares have remained unknown. To examine the biological mechanisms behind nightmares, we performed a genome-wide association study in 28,596 individuals from Finland and the United States. We identified individual genetic variants that predispose to nightmares near MYOF (rs701873, p=2.18e-8) and PTPRJ (rs11039471,p=3.7e-8), a gene previously associated with sleep duration. We found a strong genetic correlation between the frequency of nightmares and traits related to personality and psychiatric disorders; neuroticism (rg=0.59, p=8e-7), post-traumatic stress disorder (PTSD) (rg=0.58, p=0.004) as well as major depressive disorder (rg=0.68, p=7e-4), and sleep traits; and daytime sleepiness (rg=0.62, p=1e-6) and insomnia (rg=0.50, p=1.87e-5). Analysis of directionality using mendelian randomization showed a significant effect from feelings of fed-up (p=0.001), nervous (p=0.004) and miserableness (p=0.0045) to nightmares with no evidence of pleiotropy and no evidence of nightmares predisposing to psychiatric or psychological problems. Our findings suggest that nightmares are caused by unique genetic risk factors, and here we identify the first individual genetic associations. In addition, a substantial effect on nightmares is conveyed through underlying psychological and sleep problems, with psychological problems being causal for nightmares.
Ultradian regulation of rest and activity bouts in mice
Authors: Ananthasubramaniam Bharath , Meijer Johanna H. 
Published: November 2019

AbstractThe suprachiasmatic nucleus (SCN), which serves as the central pacemaker in mammals, regulates the 24-hour rhythm in behavioral activity. However, it is currently unclear whether and how bouts of activity and rest are regulated within the 24-hour cycle (i.e., over ultradian time scales). Therefore, we used passive infrared sensors to measure behavior in mice housed under either a light-dark (LD) cycle or continuous darkness (DD). We found that a probabilistic Markov model captures the ultradian changes in the behavioral state over a 24-hour cycle. In this model, the animal’s behavioral state in the next time interval is determined solely by the animal’s current behavioral state and by the “toss” of a proverbial “biased coin”. We found that the bias of this “coin” is regulated by light input and by the phase of the clock. Moreover, the bias of this “coin” for an animal is related to the average length of rest and activity bouts in that animal. In LD conditions, the average length of rest bouts was greater during the day compared to during the night, whereas the average length of activity bouts was greater during the night compared to during the day. Importantly, we also found that day-night changes in the rest bout lengths were significantly greater than day-night changes in the activity bout lengths. Finally, in DD conditions, the activity and rest bouts also differed between subjective night and subjective day, albeit to a lesser extent compared to LD conditions. The persistent differences in bout length over the circadian cycle following loss of the external LD cycle indicate that the central pacemaker plays a role in regulating rest and activity bouts on an ultradian time scale.
Marker-Trait Complete Analysis
Authors: Zhou Yi-Hui , Gallins Paul , Wright Fred 
Published: November 2019

1AbstractA recurring problem in genomics involves testing association of one or more traits of interest to multiple genomic features. Feature-trait squared correlations r2 are commonly-used statistics, sensitive to trend associations. It is often of interest to perform testing across collections {r2} over markers and/or traits using both maxima and sums. However, both trait-trait correlations and marker-marker correlations may be strong and must be considered. The primary tools for multiple testing suffer from various shortcomings, including p-value inaccuracies due to asymptotic methods that may not be applicable. Moreover, there is a lack of general tools for fast screening and follow-up of regions of interest.To address these difficulties, we propose the MTCA approach, for Marker-Trait Complete Analysis. MTCA encompasses a large number of existing approaches, and provides accurate p-values over markers and traits for maxima and sums of r2 statistics. MTCA uses the conditional inference implicit in permutation as a motivational frame-work, but provides an option for fast screening with two novel tools: (i) a multivariate-normal approximation for the max statistic, and (ii) the concept of eigenvalue-conditional moments for the sum statistic. We provide examples for gene-based association testing of a continuous phenotype and cis-eQTL analysis, but MTCA can be applied in a much wider variety of settings and platforms.
Poisson balanced spiking networks
Authors: Rullán Buxó Camille E. , Pillow Jonathan W. 
Published: November 2019

AbstractAn important problem in computational neuroscience is to understand how networks of spiking neurons can carry out various computations underlying behavior. Balanced spiking networks (BSNs) provide a powerful framework for implementing arbitrary linear dynamical systems in networks of integrate-and-fire neurons (Boerlin et al. [1]). However, the classic BSN model requires near-instantaneous transmission of spikes between neurons, which is biologically implausible. Introducing realistic synaptic delays leads to an pathological regime known as “ping-ponging”, in which different populations spike maximally in alternating time bins, causing network output to overshoot the target solution. Here we document this phenomenon and provide a novel solution: we show that a network can have realistic synaptic delays while maintaining accuracy and stability if neurons are endowed with conditionally Poisson firing. Formally, we propose two alternate formulations of Poisson balanced spiking networks: (1) a “local” framework, which replaces the hard integrate-and-fire spiking rule within each neuron by a “soft” threshold function, such that firing probability grows as a smooth nonlinear function of membrane potential; and (2) a “population” framework, which reformulates the BSN objective function in terms of expected spike counts over the entire population. We show that both approaches offer improved robustness, allowing for accurate implementation of network dynamics with realistic synaptic delays between neurons. Moreover, both models produce positive correlations between similarly tuned neurons, a feature of real neural populations that is not found in the original BSN. This work unifies balanced spiking networks with Poisson generalized linear models and suggests several promising avenues for future research.
Physiological and molecular responses of a newly evolved auxotroph of Chlamydomonas to B12 deprivation
Authors: Bunbury Freddy , Helliwell Katherine E , Mehrshahi Payam , Davey Matthew P , Salmon Deborah , Holzer Andre , Smirnoff Nicholas , Smith Alison G 
Published: November 2019

AbstractThe corrinoid B12 is synthesised only by prokaryotes yet is widely required by eukaryotes as an enzyme cofactor. Microalgae have evolved B12 dependence on multiple occasions and we previously demonstrated that experimental evolution of the non-requiring alga Chlamydomonas reinhardtii in media supplemented with B12 generated a B12-dependent mutant (hereafter metE7). This clone provides a unique opportunity to study the physiology of a nascent B12 auxotroph. Our analyses demonstrate that B12 deprivation of metE7 disrupted C1 metabolism, caused an accumulation of starch and triacylglycerides and a decrease in photosynthetic pigments, proteins and free amino acids. B12 deprivation also caused a substantial increase in reactive oxygen species (ROS), which preceded rapid cell death. Surprisingly, survival could be improved without compromising growth by simultaneously depriving the cells of nitrogen, suggesting a type of cross protection. Significantly, we found further improvements in survival under B12 limitation and an increase in B12 use-efficiency after metE7 underwent a further period of experimental evolution, this time in coculture with a B12-producing bacterium. Therefore, although an early B12-dependent alga would likely be poorly adapted to B12 deprivation, association with B12-producers can ensure long-term survival whilst also providing the environment to evolve mechanisms to better tolerate B12 limitation.
Aurora B-dependent Ndc80 Degradation Regulates Kinetochore Composition in Meiosis
Authors: Chen Jingxun , Liao Andrew , Powers Emily N , Liao Hanna , Kohlstaedt Lori A , Evans Rena , Holly Ryan M , Kim Jenny Kim , Jovanovic Marko , Ünal Elçin 
Published: November 2019

ABSTRACTThe kinetochore complex is a conserved machinery that connects chromosomes to spindle microtubules. During meiosis, the kinetochore is restructured to accommodate a specialized chromosome segregation pattern. In budding yeast, meiotic kinetochore remodeling is mediated by the temporal changes in the abundance of a single subunit called Ndc80. We have previously described the regulatory events that control the timely synthesis of Ndc80. Here, we report that Ndc80 turnover is also tightly regulated in meiosis: Ndc80 degradation is active in meiotic prophase, but not in metaphase I. Ndc80 degradation depends on the ubiquitin ligase APCAma1and is mediated by the proteasome. Importantly, Aurora B-dependent Ndc80 phosphorylation, a mark that has been previously implicated in correcting erroneous microtubule–kinetochore attachments, is essential for Ndc80 degradation in a microtubule-independent manner. The N-terminus of Ndc80, including a 27-residue sequence and Aurora B phosphorylation sites, is both necessary and sufficient for kinetochore protein degradation. Finally, defects in Ndc80 turnover predispose meiotic cells to chromosome mis-segregation. Our study elucidates the mechanism by which meiotic cells modulate their kinetochore composition through regulated Ndc80 degradation, and demonstrates that Aurora B-dependent regulation of kinetochores extends beyond altering microtubule attachments.
Mass spectrometry analysis of mouse hematopoietic stem cells and their progenitors reveals differential expression within and between proteome and transcriptome throughout adult and aged hematopoiesis
Authors: Zaro Balyn W. , Noh Joseph J. , Mascetti Victoria L. , Demeter Janos , George Benson M. , Zukowska Monika , Gulati Gunsagar S. , Sinha Rahul , Morganti Rachel M. , Banuelos Allison M. , Zhang Allison , Jackson Peter K. , Weissman Irving L. 
Published: November 2019

SummaryHematopoietic stem cells (HSCs) are responsible for the generation of blood and immune cells throughout life. They have the unique ability to self-renew and generate more HSCs or differentiate into a progenitor cell in response to cell-intrinsic and -extrinsic stimuli. The balance of HSC fate commitment is critical for a healthy blood supply. Imbalances during hematopoiesis, which are frequent in aging, can result in hematological malignancies and pre-malignancies as well as increase risk of atherosclerosis. Given the importance of HSCs and their progenitors, they have been extensively characterized in genomic and transcriptomic studies. However, an understanding of protein expression within the HSC compartment and more broadly throughout hematopoiesis remains poorly understood, and it has been widely reported that the correlation between mRNA and proteins is more complicated than previously thought. Previous mouse mass spectrometry studies have focused either specifically on stem and the first early progenitor or broadly across mixed populations of stem and progenitor cells, which do not allow for cell-type specific protein resolution across stages of differentiation. Mass cytometry has been employed to characterize transcription factor expression in human HSCs and progenitors but does not apply an unbiased discovery approach. New mass spectrometry technology now allows for deep proteomic coverage with no more than 200 ng of sample input. We report here a proteomics resource characterizing protein expression in mouse adult and aged HSCs, multipotent progenitors and oligopotent progenitors, 12 cell types in total. We validated differential expression by flow cytometry analysis and immunofluorescence staining. Additionally, we investigated the relationship between mRNA and protein levels of individual genes in HSCs compared to progenitors through RNA sequencing studies and identified two proteins that appear to be uniquely regulated in the HSC compartment, Cpin1 and Adnp. In summary, this resource provides proteomic coverage of adult and aged hematopoietic stem cells and their progenitors and reveals changes in protein abundance between cell types, with potential future implications in understanding mechanisms for stem-cell maintenance, niche interactions and fate determination.