bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development ofmPing-based Activation Tags for Crop Insertional Mutagenesis
Authors: Johnson Alexander , Mcassey Edward , Diaz Stephanie , Reagin Jacob , Parrilla Daymond R. , Nguyen Hanh , Stec Adrian , McDaniel Lauren A. L. , Clemente Thomas E. , Stupar Robert M. , Parrott Wayne A. , Hancock C. Nathan 
Published: April 2020

AbstractModern plant breeding increasingly relies on genomic information to guide crop improvement. Although some genes are characterized, additional tools are needed to effectively identify and characterize genes associated with crop traits. To address this need, themPingelement from rice was modified to serve as an activation tag to induce expression of nearby genes. Embedding promoter sequences inmPingresulted in a decrease in overall transposition rate; however, this effect was negated by using a hyperactive version ofmPingcalledmmPing20. Transgenic soybean events carryingmPing-based activation tags and the appropriate transposase expression cassettes showed evidence of transposition. Expression analysis of a line that contained a heritable insertion of themmPing20Factivation tag indicated that the activation tag induced overexpression of the nearby soybean genes. This represents a significant advance in gene discovery technology as activation tags have the potential to induce more phenotypes than the originalmPingelement, improving the overall effectiveness of the mutagenesis system.
Mask, the Drosophila Ankyrin Repeat and KH domain-containing protein, regulates microtubule dynamics
Authors: Martinez Daniel , Zhu Mingwei , Guidry Jessie J. , Majeste Niles , Mao Hui , Yanofsky Sarah , Tian Xiaolin , Wu Chunlai 
Published: April 2020

AbstractProper regulation of microtubule (MT) dynamics is vital for essential cellular processes and neuronal activities, including axonal transport as well as synaptic growth and remodeling. Here we demonstrate that Mask negatively regulates MT stability and maintains a balanced dynamics of MT length and architecture in both fly larval muscles and motor neurons. In larval muscles, loss of mask increases MT length, and genetically altering mask levels modifies the Tau-induced MT fragmentation. In motor neurons, loss of mask function reduces the number of End-Binding Protein 1 (EB1)-positive MT plus-end structures in the axons and also results in overexpansion of the presynaptic terminal at larval neuromuscular junctions (NMJs). mask shows strong genetic interaction with stathmin (stai), a neuronal modulator of MT dynamics, in regulation of axon transportation and synaptic terminal stability. Our structure/function analysis on Mask revealed that truncated Mask transgenes carrying only its N-terminal portion that contains the two Ankyrin repeats domains is able to rescue the MT-related mask loss-of-function defects in larval muscles and NMJs, suggesting an essential role of the Ankyrin repeats domains in mediating Mask’s MT stability-regulating function. Furthermore, we discovered that Mask negatively regulates the abundance of the microtubule-associated protein Jupiter in motor neuron axons, and that neuronal knocking down of Jupiter partially suppresses mask loss of function phenotypes at the larval NMJs. Together, our study identified Mask as a novel regulator for microtubule stability and dynamics.Author SummaryMicrotubules (MTs) are an essential part of the cellular cytoskeleton, providing the structural basis for critical cellular processes and functionality. A series of factors are required to orchestrate the assembly and disassembly of MTs. Here, we identified Mask as a novel regulator of MT dynamics in Drosophila. Mask shows prominent interplay with two important modulators of MT, Tau and Stathmin (Stai). These findings not only support the role of Mask as a novel microtubule regulator but also provide the foundation to explore future therapeutic strategies in mitigating deficits related to dysfunction of Tau and/or Stai, both of which are linked to human neurodegenerative disorders. Further analyses on Mask demonstrated that Jupiter’s localization to the MTs in the axons is negatively affected by Mask, and that reducing Jupiter level is able to partially suppress synaptic defects caused by mask mutant. Together, these data imply that Mask’s function in regulating MT dynamics requires Jupiter.
SwabExpress: An end-to-end protocol for extraction-free COVID-19 testing
Authors: Srivatsan Sanjay , Heidl Sarah , Pfau Brian , Martin Beth K. , Han Peter D. , Zhong Weizhi , van Raay Katrina , McDermot Evan , Opsahl Jordan , Gamboa Luis , Smith Nahum , Truong Melissa , Cho Shari , Barrow Kaitlyn A. , Rich Lucille M. , Stone Jeremy , Wolf Caitlin R. , McCulloch Denise J. , Kim Ashley E. , Brandstetter Elisabeth , Sohlberg Sarah L. , Ilcisin Misja , Geyer Rachel E. , Chen Wei , Gehring Jase ,   Seattle Flu Study Investigators, Kosuri Sriram , Bedford Trevor , Rieder Mark J. , Nickerson Deborah A. , Chu Helen Y. , Konnick Eric Q. , Debley Jason S. , Shendure Jay , Lockwood Christina M. , Starita Lea M. 
Published: April 2020

Structured AbstractBackgroundThe urgent need for massively scaled clinical testing for SARS-CoV-2, along with global shortages of critical reagents and supplies, has necessitated development of streamlined laboratory testing protocols. Conventional nucleic acid testing for SARS-CoV-2 involves collection of a clinical specimen with a nasopharyngeal swab in transport medium, nucleic acid extraction, and quantitative reverse transcription PCR (RT-qPCR) (1). As testing has scaled across the world, the global supply chain has buckled, rendering testing reagents and materials scarce (2). To address shortages, we developed SwabExpress, an end-to-end protocol developed to employ mass produced anterior nares swabs and bypass the requirement for transport media and nucleic acid extraction.MethodsWe evaluated anterior nares swabs, transported dry and eluted in low-TE buffer as a direct-to-RT-qPCR alternative to extraction-dependent viral transport media. We validated our protocol of using heat treatment for viral activation and added a proteinase K digestion step to reduce amplification interference. We tested this protocol across archived and prospectively collected swab specimens to fine-tune test performance.ResultsAfter optimization, SwabExpress has a low limit of detection at 2-4 molecules/uL, 100% sensitivity, and 99.4% specificity when compared side-by-side with a traditional RT-qPCR protocol employing extraction. On real-world specimens, SwabExpress outperforms an automated extraction system while simultaneously reducing cost and hands-on time.ConclusionSwabExpress is a simplified workflow that facilitates scaled testing for COVID-19 without sacrificing test performance. It may serve as a template for the simplification of PCR-based clinical laboratory tests, particularly in times of critical shortages during pandemics.
C. elegansepisodic swimming is driven by multifractal kinetics
Authors: Ikeda Yusaku , Jurica Peter , Kimura Hiroshi , Takagi Hiroaki , Zbigniew Struzik , Kiyono Ken , Arata Yukinobu , Sako Yasushi 
Published: April 2020

AbstractFractal scaling is a common property of temporal change in various modes of animal behavior. The molecular mechanisms of fractal scaling in animal behaviors remain largely unexplored. The nematodeC. elegansalternates between swimming and resting states in a liquid solution. Here, we report thatC. elegansepisodic swimming is characterized by scale-free kinetics with long-range temporal correlation and local temporal clusterization, which is characterized as multifractal kinetics. Residence times in actively-moving and inactive states were distributed in a power law-based scale-free manner. Multifractal analysis showed that temporal correlation and temporal clusterization were distinct between the actively-moving state and the inactive state. These results indicate thatC. elegansepisodic swimming is driven by transition between two behavioral states, in which each of two transition kinetics follows distinct multifractal kinetics. We found that a conserved behavioral modulator, cyclic GMP dependent kinase (PKG) may regulate the multifractal kinetics underlying an animal behavior. Our combinatorial analysis approach involving molecular genetics and kinetics provides a platform for the molecular dissection of the fractal nature of physiological and behavioral phenomena.
Optimal control of the COVID-19 pandemic with non-pharmaceutical interventions
Authors: Perkins T. Alex , España Guido 
Published: April 2020

AbstractThe COVID-19 pandemic has forced societies across the world to resort to social distancing to slow the spread of the SARS-CoV-2 virus. Due to the economic impacts of social distancing, there is growing desire to relax these measures. To characterize a range of possible strategies for control and to understand their consequences, we performed an optimal control analysis of a mathematical model of SARS-CoV-2 transmission. Given that the pandemic is already underway and controls have already been initiated, we calibrated our model to data from the US and focused our analysis on optimal controls from May 2020 through December 2021. We found that a major factor that differentiates strategies that prioritize lives saved versus reduced time under control is how quickly control is relaxed once social distancing restrictions expire in May 2020. Strategies that maintain control at a high level until summer 2020 allow for tapering of control thereafter and minimal deaths, whereas strategies that relax control in the short term lead to fewer options for control later and a higher likelihood of exceeding hospital capacity. Our results also highlight that the potential scope for controlling COVID-19 until a vaccine is available depends on epidemiological parameters about which there is still considerable uncertainty, including the basic reproduction number and the effectiveness of social distancing. In light of those uncertainties, our results do not constitute a quantitative forecast and instead provide a qualitative portrayal of possible outcomes from alternative approaches to control.
Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion
Authors: Sener Özge Cicek , Stender Adrian , Klemke Luisa , Stark Nadine , Isermann Tamara , Li Jinyu , Moll Ute M. , Schulz-Heddergott Ramona 
Published: April 2020

AbstractA prerequisite for gain-of-function (GOF) p53 missense mutants (mutp53) is protein stabilization. Moreover, a prerequisite for mutp53 stabilization is loss of the remaining wildtype (WT) p53 allele (loss-of-heterozygosity, p53LOH) in mutp53/+ tumors. Thus, GOF, mutp53 stabilization and p53LOH are strictly linked. However, the driving force for p53LOH is unknown. Typically, heterozygous tumors are an instable transition state. Here we identify the repressive WTp53-HSF1 axis as the driver of p53LOH.We find that the WTp53 allele in AOM/DSS-induced colorectal tumors (CRC) of p53R248Q/+mice retains its haploid transcriptional activity. Notably, WTp53 represses heat-shock factor 1 (HSF1) activity, the master transcription factor of the proteotoxic stress defense response (HSR) that is ubiquitously and constitutively activated in cancer tissues. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining murine CRC tumors and tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 transcriptional program.Mechanistically, the retained WTp53 allele activates CDKN1A/p21, leading to cell cycle inhibition and suppression of the E2F target gene MLK3. MLK3 links cell cycle to the MAPK stress pathway to activate the HSR response. We show that in p53R248Q/+tumors WTp53 activation by constitutive stress (emanating from proliferative/metabolic stresses and genomic instability) represses MLK3, consequently inactivating the MAPK-HSF1 response necessary to ensure tumor survival. This creates strong selection pressure for p53LOH which eliminates the repressive WTp53-HSF1 axis and unleashes the tumor-promoting HSF1 functions, inducing mutp53 stabilization and enabling invasion.HIGHLIGHTSheterozygous p53R248Q/+tumors retain p53 transcriptional activity in a mouse model of colorectal cancer (CRC)wildtype p53 actively represses the tumor-promoting HSF1-regulated chaperone system and proteotoxic stress responsethe repressive WTp53 – HSF1 axis creates a selective pressure for WTp53 loss-of-heterozygosity in CRC tumorsp53 loss-of-heterozygosity enables stabilization of the gain-of-function p53R248Qmutant protein which in turn enables CRC invasion
Adaptive evolution of hybrid bacteria by horizontal gene transfer
Authors: Power Jeffrey J. , Pinheiro Fernanda , Pompei Simone , Kovacova Viera , Yüksel Melih , Rathmann Isabel , Förster Mona , Lässig Michael , Maier Berenike 
Published: April 2020

AbstractHorizontal gene transfer is an important factor in bacterial evolution that can act across species boundaries. Yet, we know little about rate and genomic targets of cross-lineage gene transfer, and about its effects on the recipient organism’s physiology and fitness. Here, we address these questions in a parallel evolution experiment with twoBacillus subtilislineages of 7% sequence divergence. We observe rapid evolution of hybrid organisms: gene transfer swaps ~12% of the core genome in just 200 generations, and 60% of core genes are replaced in at least one population. By genomics, transcriptomics, fitness assays, and statistical modeling, we show that transfer generates adaptive evolution and functional alterations in hybrids. Specifically, our experiments reveal a strong, repeatable fitness increase of evolved populations in the stationary growth phase. By genomic analysis of the transfer statistics across replicate populations, we infer that selection on HGT has a broad genetic basis: 40% of the observed transfers are adaptive. At the level of functional gene networks, we find signatures of negative and positive selection, consistent with hybrid incompatibilities and adaptive evolution of network functions. Our results suggest that gene transfer navigates a complex cross-lineage fitness landscape, bridging epistatic barriers along multiple high-fitness paths.Significance statementIn a parallel evolution experiment, we probe lateral gene transfer between twoBacillus subtilislineages close to the species boundary. We show that laboratory evolution by horizontal gene transfer can rapidly generate hybrid organisms with broad genomic and functional alterations. By combining genomics, transcriptomics, fitness assays and statistical modeling, we map the selective effects underlying gene transfer. We show that transfer takes place under genome-wide positive and negative selection, generating a net fitness increase in hybrids. The evolutionary dynamics efficiently navigates this fitness landscape, finding viable paths with increasing fraction of transferred genes.
The genetic variation of lactase persistence alleles in northeast Africa
Authors: Hollfelder Nina , Babiker Hiba , Granehäll Lena , Schlebusch Carina M , Jakobsson Mattias 
Published: April 2020

AbstractLactase persistence (LP) is a well-studied example of a Mendelian trait under selection in some human groups due to gene-culture co-evolution. We investigated the frequencies of genetic variants linked to LP in Sudanese and South Sudanese populations. These populations have diverse subsistence patterns, and some are dependent on milk to various extents, not only from cows, but also from other livestock such as camels and goats. We sequenced a 316bp region involved in regulating the expression of theLCTgene on chromosome 2, which encompasses five polymorphisms that have been associated with LP. Pastoralist populations showed a higher frequency of LP-associated alleles compared to non-pastoralist groups, hinting at positive selection also in northeast African pastoralists. There was no incidence of the East African LP allele (−14010:C) in the Sudanese groups, and only one heterozygote individual for the European LP allele (−13910:T), suggesting limited recent admixture from these geographic regions. Among the LP variants, the −14009:G variant occurs at the highest frequency among the investigated populations, followed by the −13915:G variant, which is likely of Middle Eastern origin, consistent with Middle Eastern gene-flow to the Sudanese populations. The Beja population of the Beni Amer show three different LP-variants at substantial and similar levels, resulting in one of the greatest frequencies of LP-variants among all populations across the world.
Predictive coding as a unifying principle for explaining a broad range of brightness phenomena
Authors: Lerer Alejandro , Supèr Hans , S.Keil Matthias 
Published: April 2020

AbstractThe visual system is highly sensitive to spatial context for encoding luminance patterns. Context sensitivity inspired the proposal of many neural mechanisms for explaining the perception of luminance (brightness). Here we propose a novel computational model for estimating the brightness of many visual illusions. We hypothesize that many aspects of brightness can be explained by a predictive coding mechanism, which reduces the redundancy in edge representations on the one hand, while non-redundant activity is enhanced on the other (response equalization). Response equalization is implemented with a dynamic filtering process, which (dynamically) adapts to each input image. Dynamic filtering is applied to the responses of complex cells in order to build a gain control map. The gain control map then acts on simple cell responses before they are used to create a brightness map via activity propagation. Our approach is successful in predicting many challenging visual illusions, including contrast effects, assimilation, and reverse contrast.Author summaryWe hardly notice that what we see is often different from the physical world “outside” of the brain. This means that the visual experience that the brain actively constructs may be different from the actual physical properties of objects in the world. In this work, we propose a hypothesis about how the visual system of the brain may construct a representation for achromatic images. Since this process is not unambiguous, sometimes we notice “errors” in our perception, which cause visual illusions. The challenge for theorists, therefore, is to propose computational principles that recreate a large number of visual illusions and to explain why they occur. Notably, our proposed mechanism explains a broader set of visual illusions than any previously published proposal. We achieved this by trying to suppress predictable information. For example, if an image contained repetitive structures, then these structures are predictable and would be suppressed. In this way, non-predictable structures stand out. Predictive coding mechanisms act as early as in the retina (which enhances luminance changes but suppresses uniform regions of luminance), and our computational model holds that this principle also acts at the next stage in the visual system, where representations of perceived luminance (brightness) are created.
Body mass index trajectories and adiposity rebound during the first 6 years in Korean children: based on the National Health Information Database, 2008-2015
Authors: Hwang Il Tae , Ju Young-Su , Lee Hye Jin , Shim Young Suk , Jeong Hwal Rim , Kang Min Jae 
Published: April 2020

AbstractPurposeWe analyzed the nationwide longitudinal data to explore body mass index (BMI) growth trajectories and the time of adiposity rebound (AR).MethodsPersonal data of 84,005 subjects born between 2008 and 2012 were obtained from infant health check-ups which were performed at 5, 11, 21, 33, 45, 57, and 69 months. BMI 00trajectories of each subject were made according to sex and birth weight (Bwt) and the timing of AR was defined as the lowest BMI occurred. Subjects were divided according to Bwt and AR timing as follows: very low birth weight (VLBW), 0.5 kg ≤ Bwt ≤ 1.5 kg; low birth weight (LBW), 1.5 kg < Bwt ≤ 2.5 kg; non-LBW, 2.5 kg < Bwt ≤ 5.0 kg; early AR, before 45 months; moderate AR, at 57 months; and late AR, not until 69 months.Main resultsMedian time point of minimum BMI was 45 months, and the prevalence rates of early, moderate, and late AR were 63.0%, 16.6%, and 20.4%, respectively. BMI at the age of 57 months showed a strong correlation with AR timing after controlling for Bwt (P< 0.001). Sugar-sweetened beverage intake at 21 months (P= 0.02) and no-exercise habit at 57 months (P< 0.001) showed correlations with early AR. When VLBW and LBW subjects were analyzed, BMI at 57 months and breastfeeding at 11 months were correlated with rapid weight gain during the first 5 months (bothP< 0.001).ConclusionsBased on this first longitudinal study, the majority of children showed AR before 57 months and the degree of obesity at the age of 57 months had a close correlation with early AR or early weight during infancy.
DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination
Authors: Crowe Jennifer L. , Wang Xiaobin S. , Shao Zhengping , Lee Brian J. , Estes Verna , Zha Shan 
Published: April 2020

AbstractThe DNA-dependent protein kinase (DNA-PK), composed of the KU heterodimer and the large catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor. Naïve B cells undergo class switch recombination (CSR) to generate antibodies with different isotypes by joining two DNA double-strand breaks at different switching regions via the cNHEJ pathway. DNA-PK and the cNHEJ pathway play important roles in the DNA repair phase of CSR. To initiate cNHEJ, KU binds to DNA ends, and recruits and activates DNA-PK. DNA-PKcs is the best-characterized substrate of DNA-PK, which phosphorylates DNA-PKcs at both the S2056 and T2609 clusters. Loss of T2609 cluster phosphorylation increases radiation sensitivity, suggesting a role of T2609 phosphorylation in DNA repair. Using theDNA-PKcs5Amouse model carrying an alanine substitution at the T2609 cluster, here we show that loss of T2609 phosphorylation of DNA-PKcs does not affect the CSR efficiency. Yet, the CSR junctions recovered fromDNA-PKcs5A/5AB cells reveal increased chromosomal translocation, excess end-resection, and preferential usage of micro-homology – all signs of the alternative end-joining pathway. Thus, these results uncover a role of DNA-PKcs T2609 phosphorylation in promoting cNHEJ repair pathway choice during CSR.Key pointsLoss of T2069 cluster phosphorylation of DNA-PKcs promotes Alt-EJ-mediated CSR.