bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of promoter methylation and transcriptional gene silencing upon high pressure spraying of 24-nt small RNAs in Nicotiana benthamiana
Authors: Walz Melanie , Hohenwarter Linus , Krczal Gabi , Wassenegger Michael , Uslu Veli Vural 
Published: March 2022

ABSTRACTExogenous RNA application is a promising transgene-free approach for crop protection and improvement. In almost all applications reported so far, exogenous RNA molecules (double stranded RNAs or small RNAs) are applied to plants in order to trigger degradation of a given mRNA (of plant, pest or pathogen origin), in a process termed post-transcriptional gene silencing (PTGS). However, whether exogenous RNAs can also trigger epigenetic modifications to plants such as RNA-directed DNA methylation (RdDM) and transcriptional gene silencing (TGS) remains largely unaddressed. Here, we provide evidence that high pressure spraying of a 24-nt short interfering RNA (siRNA) designed to target the CaMV 35S promoter that drives the expression of a GFP transgene, resulted in promoter RdDM in N. benthamiana. Moreover, the methylation at the target site spreads both up and downstream neighboring sites. Importantly, GFP expression was reduced in the sprayed leaf tissues. Small RNA sequencing excluded the presence siRNAs mapping to the GFP gene body and documented substantial amount of secondary RNAs in the promoter, suggesting that the GFP silencing was transcriptional rather than post-transcriptional. Our study provides a proof of principle for spray induced epigenetic modification (SPIEM) that could be used in modern crop breeding platforms.
Model-guided design of the diversity of a synthetic human gut community
Authors: Connors Bryce M. , Ertmer Sarah , Clark Ryan L. , Thompson Jaron , Pfleger Brian F. , Venturelli Ophelia S. 
Published: March 2022

ABSTRACTMicrobial communities have tremendous potential as therapeutics. However, a major bottleneck is manufacturing high-diversity microbial communities with desired species compositions. We develop a two-stage, model-guided framework to produce microbial communities with target species compositions. We apply this method to optimize the diversity of a synthetic human gut community. The first stage exploits media components to enable uniform growth responses of individual species and the second stage uses a design-test-learn cycle with initial species abundance as a control point to manipulate community composition. Our designed culture conditions yield 91% of the maximum possible diversity. Leveraging these data, we construct a dynamic ecological model to guide the design of lower-order communities with desired temporal properties over a longer timescale. In sum, a deeper understanding of how microbial community assembly responds to changes in environmental factors, initial species abundances, and inter-species interactions can enable the predictable design of community dynamics.
Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum
Authors: Webster Rebecca , Mitchell Hayley , Peters Jenny M. , Heunis Juanita , O’Neill Brighid , Gower Jeremy , Lynch Sean , Jennings Helen , Amante Fiona H. , Llewellyn Stacey , Marquart Louise , Potter Adam J. , Birrell Geoffrey W. , Edstein Michael D. , Shanks G. Dennis , McCarthy James S. , Barber Bridget E. 
Published: March 2022

ABSTRACTBackgroundBlocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low dose tafenoquine.MethodsHealthy adults were inoculated with P. falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50 mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays pre-dose and at 1, 4 and 7 days post-dose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia post-tafenoquine, and safety parameters.ResultsSix participants were enrolled, and all were infective to mosquitoes pre-tafenoquine, with a median 86% (range: 22–98) of mosquitoes positive for oocysts and 57% (range: 4–92) positive for sporozoites. By day 4 post-tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (IQR: 16–46) and 52% (IQR: 40–62), respectively, and by day 7, 81% (IQR 36–92) and 77% (IQR 52–98), respectively. The decline in gametocyte density post-tafenoquine was not significant. No significant participant safety concerns were identified.ConclusionLow dose tafenoquine reduces P. falciparum transmission to mosquitoes, with a delay in effect.Trial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000995976).FundingQIMR Berghofer Medical Research Institute.
Hibernation shows no apparent effect on germline mutation rates in grizzly bears
Authors: Wang Richard J. , Peña-Garcia Yadira , Bibby Madeleine , Raveendran Muthuswamy , Harris R. Alan , Jansen Heiko T. , Robbins Charles T. , Rogers Jeffrey , Kelley Joanna L. , Hahn Matthew W. 
Published: March 2022

AbstractA male mutation bias is observed across vertebrates, and, where data are available, this bias is accompanied by increased per-generation mutation rates with parental age. While continuing mitotic cell division in the male germline post-puberty has been proposed as the major cellular mechanism underlying both patterns, little direct evidence for this role has been found. Understanding the evolution of the per-generation mutation rate among species requires that we identify the molecular mechanisms that change between species. Here, we study the per-generation mutation rate in an extended pedigree of the brown (grizzly) bear, Ursus arctos horribilis. Brown bears hibernate for one-third of the year, a period during which spermatogenesis slows or stops altogether. The cessation of spermatogenesis is predicted to lessen the male mutation bias and to lower the per-generation mutation rate in this species. However, using whole-genome sequencing, we find that both male bias and per-generation mutation rates are the same as expected for a non-hibernating species. We also carry out a phylogenetic comparison of substitution rates along the lineage leading to brown bear and panda (a non-hibernating species) and find no slowing of the substitution rate in the hibernator. Our results contribute to accumulating evidence that suggests that male germline cell division is not the major determinant of mutation rates and mutation biases. The results also provide a quantitative basis for improved estimates of the timing of carnivore evolution.
Inbreeding depression in an outbred nine-spined stickleback (Pungitius pungitius) population
Authors: Fraimout Antoine , Rastas Pasi , Lv Lei , Merilä Juha 
Published: March 2022

AbstractInbreeding depression refers to the reduced fitness of offspring produced by related individuals and is expected to be rare in large outbred populations. When it occurs, marked fitness loss is possible as large populations can carry large loads of recessive harmful mutations which are normally sheltered at the heterozygous state. Using experimental cross data and genome-wide identity-by-descent (IBD) relationships from an outbred marine nine-spined stickleback (Pungitius pungitius) population, we documented a significant decrease in offspring survival probability with increasing parental IBD sharing associated with an average inbreeding load (B) of 15.896. Interestingly, we found that this relationship was also underlined by a positive effect of paternal inbreeding coefficient on offspring survival, suggesting that certain combinations of parental inbreeding and genetic relatedness among mates may promote offspring survival. Apart from demonstrating substantial inbreeding load in an outbred population, the results also highlight the potential caveat associated with artificial establishment of families in experimental studies: wild founder individuals are often - and perhaps mistakenly - assumed to be unrelated.
Hybrid-derived weedy rice maintains adaptive combinations of alleles associated with seed dormancy
Authors: Imaizumi Toshiyuki , Kawahara Yoshihiro , Auge Gabriela 
Published: March 2022

AbstractHybridization is a widespread phenomenon in plants and is a pathway for the evolution of adaptive traits. However, this process may also affect the persistence of combinations of adaptive alleles evolved through natural selection when hybridization occurs between adapted and non-adapted populations. Hybridization between weedy and cultivated rice has been confirmed with an adaptive introgression of deep seed dormancy alleles from cultivated rice. In this study, we explored the influence of hybridization on the conservation of combinations of adaptive alleles by evaluating the natural variation in and the genetic structure of genomic regions associated with seed dormancy. Based on sequence variation in the genomic regions associated with seed dormancy, we revealed that hybrid-derived weedy rice strains maintained most of the adaptive combinations for this trait that were observed in the parental weedy rice, despite equal representation of the parental weedy and cultivated rice in the whole genome sequence. Moreover, the hybrid-derived weedy rice strains had deeper seed dormancy than their parental weedy rice strains. This study suggests that hybridization between weedy rice (having adaptive allelic combinations for seed dormancy) and cultivated rice (having non-adaptive combinations) generates weedy rice strains that express deep seed dormancy caused by genome stabilization through the removal of alleles derived from cultivated rice, in addition to the adaptive introgression of deep seed dormancy alleles derived from cultivated rice. Thus, hybridization between adapted and non-adapted populations seems to be reinforcing the trajectory towards the evolution of adaptive traits.
Targeting Cblb-Notch1 axis as a novel immunotherapeutic strategy to boost CD8+ T-cells responses
Authors: Monticone Giulia , Csibi Fred , Leit Silvana , Ciccone David , Champhekar Ameya S. , Austin Jermaine E. , Ucar Deniz A. , Hossain Fokhrul , Huang Zhi , Ibba Salome V. , Boulares A. Hamid , Carpino Nicholas , Majumder Samarpan , Xu Keli , Osborne Barbara A. , Loh Christine , Miele Lucio 
Published: March 2022

AbstractA critical feature of cancer is the ability to induce immunosuppression and evade immune responses. Tumor-induced immunosuppression diminishes the efficacy of endogenous immune responses and decreases the efficacy of cancer immunotherapy. In this study, we describe a new immunosuppressive pathway in which adenosine promotes Cbl-b-mediated Notch1 degradation, causing suppression of CD8+ T-cells effector functions. Genetic KO and pharmacological inhibition of Cbl-b prevents Notch1 degradation in response to adenosine and reactivates its signaling. Reactivation of Notch1 results in enhanced CD8+ T-cell effector functions, anti-cancer response and resistance to immunosuppression. Our work demonstrates that targeting Cbl-b-Notch1 axis is a novel promising strategy for cancer immunotherapy.
Limited effects of age on the use of the ankle and counter-rotation mechanism in the sagittal plane
Authors: van den Bogaart Maud , Bruijn Sjoerd M. , Spildooren Joke , van Dieën Jaap H. , Meyns Pieter 
Published: March 2022

AbstractTwo mechanisms can be used to accelerate the center of mass (CoM) to control the CoM in relation to the base of support during standing. The first is applying ankle moments to shift the center of pressure (CoP), which has been coined the “CoP mechanism”. The second is changing the angular momentum around the CoM to change the direction of the ground reaction force, i.e., the “counter-rotation mechanism”. At both the beginning and the end of the lifespan, problems with postural control are common. In this study, we asessed anteroposterior balance performance and the related use of these postural control mechanisms in children, younger adults, and older adults. Sixteen pre-pubertal children (6-9y), 17 younger adults (18-24y) and eight older adults (65-80y) performed bipedal upright standing trials of 16 seconds on a rigid surface and on three balance boards that could freely move in the sagittal plane, varying in height (15-19 cm) of the board above the point of contact with the floor. Full body kinematics were measured. Performance related outcome measures, i.e., the number of trials with balance loss and the Root Mean Square (RMS) of the time series of the CoM acceleration were calculated. Additionally, the RMS of the time series of the CoM acceleration due to the CoP and counter-rotation mechanism and the contributions of the CoP and the counter-rotation mechanism to the CoM acceleration (in %) in the sagittal plane were calculated. Furthermore, selected kinematic measures, i.e., the orientation of the board and the head and the Mean Power Frequency of balance board orientation and of CoM acceleration were calculated. Compared to younger adults, children and older adults showed a poorer balance performance, reflected by a greater RMS of CoM accelerations and more balance loss in older adults. Across age groups and conditions, the contribution of the CoP mechanism to the total CoM acceleration was dominant, i.e., 95%-108%. The contribution of the counter-rotation mechanism ranged between 19%-31% (with totals higher than 100% indicating opposite effects of both mechanisms). We suggest that the contribution of the counter-rotation mechanism is limited, since the counter-rotation mechanism would conflict with stabilizing the orientation of the head in space. Furthermore, children did use the counter-rotation mechanism relatively more to accelerate the CoM compared to younger adults. Possibly this reflects that they are still learning to limit the contribution of the counter-rotation mechanism to the same extent as adults.
Noninvasive stimulation of the ventromedial prefrontal cortex modulates rationality of human decision-making
Authors: Kroker Thomas , Wyczesany Miroslaw , Rehbein Maimu Alissa , Roesmann Kati , Wessing Ida , Junghöfer Markus 
Published: March 2022

SummaryThe framing-effect is a bias that affects decision-making depending on whether the available options are presented with positive or negative connotations. Even when the outcome of two choices is equivalent, people have a strong tendency to avoid the negatively framed option because losses are perceived about twice as salient as gains of the same amount (i.e. loss-aversion). The ventromedial prefrontal cortex (vmPFC) is crucial for rational decision-making, and dysfunctions in this region have been linked to cognitive biases, impulsive behavior and gambling addiction. Using a financial decision-making task in combination with magnetoencephalographic neuroimaging, we show that excitatory compared to inhibitory non-invasive transcranial direct current stimulation (tDCS) of the vmPFC reduces framing-effects while improving the assessment of loss-probabilities, ultimately leading to increased overall gains. Behavioral and neural data consistently suggest that this improvement in rational decision-making is predominately a consequence of reduced loss-aversion. These findings recommend further research towards clinical applications of vmPFC-tDCS in addictive disorders.
Predictable and stable epimutations induced during clonal propagation with embryonic transcription factors
Authors: Wibowo Anjar Tri , Antunez-Sanchez Javier , Dawson Alexander , Price Jonathan , Meehan Cathal , Wrightsman Travis , Collenberg Maximillian , Bezrukov Ilja , Becker Claude , Benhamed Moussa , Weigel Detlef , Gutierrez-Marcos Jose 
Published: March 2022

AbstractAlthough clonal propagation is frequently used in commercial plant breeding and plant biotechnology programs because it minimizes genetic variation, it is not uncommon to observe clonal plants with stable phenotypic changes, a phenomenon known as somaclonal variation. Several studies have shown that epigenetic modifications induced during regeneration are associated with this newly acquired phenotypic variation. However, the factors that determine the extent of somaclonal variation and the molecular changes associated with it remain poorly understood. To address this gap in our knowledge, we compared clonally propagatedArabidopsis thalianaplants derived from somatic embryogenesis using two different embryonic transcription factors-RWP-RK DOMAIN-CONTAINING 4 (RKD4)orLEAFY COTYLEDON2 (LEC2)and from two epigenetically distinct tissues. We found that both the epi(genetic) status of explant and the regeneration protocol employed play critical roles in shaping the molecular and phenotypic state of clonal plants. Phenotypic variation of regenerated plants can be largely explained by the inheritance of tissue-specific DNA methylation imprints, which are associated with specific transcriptional and metabolic changes in sexual progeny of clonal plants. Moreover, regenerants from roots were particularly affected by the inheritance of epigenetic imprints, which resulted in increased accumulation of salicylic acid in leaves and accelerated plant senescence. Collectively, our data reveal pathways for targeted manipulation of phenotypic variation in clonal plants.
Fluximplied: A novel approach integrates rate limiting steps and differential expression for pathway analysis
Authors: Sportiello Mike , Geber Adam , Palli Rohith , Embong A Karim , Laniewski Nathan G. , Reilly Emma C. , Emo Kris Lambert , Topham David J. 
Published: March 2022

AbstractBackgroundMany tools exist to perform a rigorous pathway analysis, though traditional gene set enrichment analysis remains among the most common. While useful for many applications, one common situation where it is less so is the metabolic profiling of bulk omics datasets. Rate limiting steps in more linear pathways are the main determinant of flux through these pathways, but differential expression of the enzymes that catalyze these steps is usually not differentially weighted in pathway analysis. Fluximplied was built to perform pathway analysis with rate limiting steps in mind to assess the implied flux through a number of well validated metabolic pathways.ResultsA database of rate limiting steps and their associated pathway was constructed. Using publicly available human RNA sequencing data from liver, putamen, and adipose tissue, fluximplied generally corroborated the pathway analysis. When comparing two CD8 T cell subsets from mouse lung, our algorithm confirmed previous findings that were not found previously.ConclusionFluximplied is an accessible tool for pathway analysis which is intended to assist the user with hypothesis generation. Unlike traditional approaches to pathway analysis, it specifically queries a database of rate limiting steps in order to infer flux through canonical metabolic pathways.
Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
Authors: Hochuli Joshua E. , Jain Sankalp , Melo-Filho Cleber , Sessions Zoe L. , Bobrowski Tesia , Choe Jun , Zheng Johnny , Eastman Richard , Talley Daniel C. , Rai Ganesha , Simeonov Anton , Tropsha Alexander , Muratov Eugene N. , Baljinnyam Bolormaa , Zakharov Alexey V. 
Published: March 2022

AbstractThe COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2’s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection.Abstract FigureTOC Graphic: Overall study design.
Quorum sensing as a mechanism to harness the wisdom of the crowds
Authors: Moreno-Gámez Stefany , Hochberg Michael E. , van Doorn G. S. 
Published: March 2022

AbstractBacteria release and sense small molecules called autoinducers (AIs) in a process known as ‘quorum sensing’ (QS). The prevailing interpretation of QS is that by sensing AI concentrations, bacteria estimate population density to regulate the expression of functions that are only beneficial when carried out by a sufficiently large number of cells. However, a major challenge to this interpretation is that the concentration of AIs strongly depends on the environment, often rendering AI-based estimates of cell density unreliable. Here we propose an alternative interpretation of QS, where bacteria, by releasing and sensing AIs, harness social interactions to sense the environment as a collective. As shown by a model, this functionality can explain the evolution of QS, and results from individuals improving their estimation accuracy by pooling many imperfect estimates – analogous to the ‘wisdom of the crowds’ in decision theory. Importantly, our model reconciles the observed dependence of QS on both population density and the environment and explains why several QS systems regulate the production of private goods.
Leaf bacterial community structure and variation in wild ruderal plants are shaped by the interaction of host species and defense chemistry with environment
Authors: Mayer Teresa , Reichelt Michael , Gershenzon Jonathan , Agler Matthew 
Published: March 2022

SummaryVariable phenotypes help plants ensure fitness and survival in the face of unpredictable environmental stresses. Leaf bacteria (bacteriomes) can extend plant phenotypes and are well-known to vary from one plant to the next, but little is known about controls on this variation. Here, we find in 9 populations of Arabidopsis thaliana that core leaf bacteriomes are largely, but not completely, shared with other ground-dwelling ruderal plant species. Strength of differentiation between plant species and between A. thaliana populations shifts from year to year, becoming stronger when plants within populations have more similar leaf bacteriomes (less plant-to-plant variation or stochasticity). Interestingly, across different populations, plants with shared leaf aliphatic glucosinolate chemotypes exhibited similar strong year-to-year stochasticity shifts. Therefore, stochasticity of leaf bacteriomes in plant populations changes in specific ways and might be controlled by plant traits, with important implications for how plants adapt to complex and shifting environments.