Expression of human ARGONAUTE 2 inhibits endogenous microRNA activity in Arabidopsis

Plant and animal microRNA (miRNA) pathways share many analogous components, the ARGONAUTE (AGO) proteins being foremost among them. We sought to ascertain the degree of functional conservation shared by Homo sapiens ARGONAUTE 2 (HsAGO2) and Arabidopsis thaliana ARGONAUTE 1 (AtAGO1), which are the predominant AGO family members involved with miRNA activity in their respective species. Transgenic Arabidopsis plants expressing HsAGO2 were indistinguishable from counterparts over-expressing AtAGO1, each group exhibiting the morphological and molecular hallmarks of miRNA-pathway loss-of-function alleles. However, unlike AtAGO1, HsAGO2 was unable to rescue the ago1-27 allele. We conclude that, despite the evolutionary gulf between them, HsAGO2 is likely capable of interacting with some component/s of the Arabidopsis miRNA pathway, thereby perturbing its operation, although differences have arisen such that HsAGO2 alone is insufficient to confer efficient silencing of miRNA targets in planta

Modeling spatiotemporal dynamics of outbreaking species: influence of environment and migration in a locust

Many pest species exhibit huge fluctuations in population abundance. Understanding their large-scale and long-term dynamics is necessary to develop effective control and management strategies. Occupancy models represent a promising approach to unravel interactions between environmental factors and spatiotemporal dynamics of outbreaking populations. Here, we investigated population dynamics of the Australian plague locust, Chortoicetes terminifera, using density data collected between 1988 and 2010 by the Australian Plague Locust Commission over more than 3 million km2 in eastern Australia. We applied multistate and autologistic multi-season occupancy models to test competing hypotheses about environmental and demographic processes affecting the large-scale dynamics of the Australian plague locust. We found that rainfall and land cover predictors best explained the spatial variability in outbreak probability across eastern Australia. Outbreaks are more likely to occur in temperate than tropical regions, with a faster and more continuous response to rainfall in desert than in agricultural areas. Our results also support the hypothesis that migration tends to propagate outbreaks only locally (over distances lower than 400 km) rather than across climatic regions. Our study suggests that locust outbreak forecasting and management systems could be improved by implementing key environmental factors and migration in hierarchical spatial models. Finally, our modeling framework can be seen as a step towards bridging the gap between mechanistic and more phenomenological models in the spatial analysis of fluctuating populations

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction

Universal Alternative Splicing of Noncoding Exons

The human transcriptome is so large, diverse, and dynamic that, even after a decade of investigation by RNA sequencing (RNA-seq), we have yet to resolve its true dimensions. RNA-seq suffers from an expression-dependent bias that impedes characterization of low-abundance transcripts. We performed targeted single-molecule and short-read RNA-seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome, identifying a fundamental distinction between protein-coding and noncoding gene content: almost every noncoding exon undergoes alternative splicing, producing a seemingly limitless variety of isoforms. Analysis of syntenic regions of the mouse genome shows that few noncoding exons are shared between human and mouse, yet human splicing profiles are recapitulated on Hsa21 in mouse cells, indicative of regulation by a deeply conserved splicing code. We propose that noncoding exons are functionally modular, with alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for gene evolution

Parallel laboratory evolution and rational debugging reveal genomic plasticity to S. cerevisiae synthetic chromosome XIV defects

Synthetic chromosome engineering is a complex process due to the need to identify and repair growth defects and deal with combinatorial gene essentiality when rearranging chromosomes. To alleviate these issues, we have demonstrated novel approaches for repairing and rearranging synthetic Saccharomyces cerevisiae genomes. We have designed, constructed, and restored wild-type fitness to a synthetic 753,096-bp version of S. cerevisiae chromosome XIV as part of the Synthetic Yeast Genome project. In parallel to the use of rational engineering approaches to restore wild-type fitness, we used adaptive laboratory evolution to generate a general growth-defect-suppressor rearrangement in the form of increased TAR1 copy number. We also extended the utility of the synthetic chromosome recombination and modification by loxPsym-mediated evolution (SCRaMbLE) system by engineering synthetic-wild-type tetraploid hybrid strains that buffer against essential gene loss, highlighting the plasticity of the S. cerevisiae genome in the presence of rational and non-rational modifications. </p

Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions

BackgroundTargeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing.ResultsAll panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden.ConclusionThis comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.Peer reviewe

Extreme events are more likely to affect the breeding success of lesser kestrels than average climate change

Climate change is predicted to severely impact interactions between prey, predators and habitats. In Southern Europe, within the Mediterranean climate, herbaceous vegetation achieves its maximum growth in middle spring followed by a three-month dry summer, limiting prey availability for insectivorous birds. Lesser kestrels (Falco naumanni) breed in a time-window that matches the nestling-rearing period with the peak abundance of grasshoppers and forecasted climate change may impact reproductive success through changes in prey availability and abundance. We used Normalised Difference Vegetation Index (NDVI) as a surrogate of habitat quality and prey availability to investigate the impacts of forecasted climate change and extreme climatic events on lesser kestrel breeding performance. First, using 14 years of data from 15 colonies in Southwestern Iberia, we linked fledging success and climatic variables with NDVI, and secondly, based on these relationships and according to climatic scenarios for 2050 and 2070, forecasted NDVI and fledging success. Finally, we evaluated how fledging success was influenced by drought events since 2004. Despite predicting a decrease in vegetation greenness in lesser kestrel foraging areas during spring, we found no impacts of predicted gradual rise in temperature and decline in precipitation on their fledging success. Notwithstanding, we found a decrease of 12% in offspring survival associated with drought events, suggesting that a higher frequency of droughts might, in the future, jeopardize the recent recovery of the European population. Here, we show that extreme events, such as droughts, can have more significant impacts on species than gradual climatic changes, especially in regions like the Mediterranean Basin, a biodiversity and climate change hotspotinfo:eu-repo/semantics/publishedVersio

Global perspectives and transdisciplinary opportunities for locust and grasshopper pest management and research

Locusts and other migratory grasshoppers are transboundary pests. Monitoring and control, therefore, involve a complex system made up of social, ecological, and technological factors. Researchers and those involved in active management are calling for more integration between these siloed but often interrelated sectors. In this paper, we bring together 38 coauthors from six continents and 34 unique organizations, representing much of the social-ecological-technological system (SETS) related to grasshopper and locust management and research around the globe, to introduce current topics of interest and review recent advancements. Together, the paper explores the relationships, strengths, and weaknesses of the organizations responsible for the management of major locust-affected regions. The authors cover topics spanning humanities, social science, and the history of locust biological research and offer insights and approaches for the future of collaborative sustainable locust management. These perspectives will help support sustainable locust management, which still faces immense challenges such as fluctuations in funding, focus, isolated agendas, trust, communication, transparency, pesticide use, and environmental and human health standards. Arizona State University launched the Global Locust Initiative (GLI) in 2018 as a response to some of these challenges. The GLI welcomes individuals with interests in locusts and grasshoppers, transboundary pests, integrated pest management, landscape-level processes, food security, and/or cross-sectoral initiatives