Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine ...deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.
Display omitted
•A pipeline to maximize recovery of SNPs from RADseq in non-model organisms was developed.•Phylogenomic relationships within tribe Shoreeae (Dipterocarpaceae) were inferred.•Genus ...Shorea sensu Ashton is not monophyletic.•Shorea can be divided into groups corresponding to morphological classifications.•Ancestral state reconstructions of floral traits give insights into floral evolution.
A supra-annual, community-level synchronous flowering prevails in several parts of the tropical forests of Southeast Asia and its evolution has been hypothesized to be linked to pollinator shifts. The aseasonal Southeast Asian lowland rainforests are dominated by Dipterocarpaceae, which exhibit great floral diversity, a range of pollination syndromes and include species with annual and supra-annual gregarious flowering. Phylogenetic relationships within this family are still unclear, especially in the tribe Shoreeae. Here, we develop a pipeline to maximize recovery of genome-wide SNPs from restriction-site associated DNA sequencing (RADseq) in non-model organisms across wide phylogenetic scales. We then infer phylogenomic relationships in the tribe Shoreeae using both traditional and coalescent analyses. The phylogenetic trees obtained with these methods are congruent to each other and highly resolved. They allow reconstructing the evolutionary patterns of floral traits (number of stamens, anther structure and anther/appendage size) in the group. Our inferences indicate that species with many stamens, but smaller, globose anthers and longer appendages and have evolved multiple times from species with fewer stamens, but larger, oblong anthers and shorter appendages. This could have happened in parallel to iterative shifts in pollinators across the uncovered phylogeny from larger, longer generation to smaller, shorter-generation insects that can quickly build up the necessary population sizes during mass flowering episodes.
The Krüppel-like family of transcription factors plays critical roles in human development and is associated with cancer pathogenesis. Krüppel-like factor 5 gene (
) has been shown to promote cancer ...cell proliferation and tumorigenesis and to be genomically amplified in cancer cells. We recently reported that the
gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here, we show that these alterations activate KLF5 by three distinct mechanisms: (i) Focal amplification of superenhancers activates
expression in squamous cell carcinomas; (ii) Missense mutations disrupt KLF5-FBXW7 interactions to increase KLF5 protein stability in colorectal cancer; (iii) Cancer type-specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with
overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target.
Our observations, together with previous studies that identified oncogenic properties of KLF5, establish the importance of KLF5 activation in human cancers, delineate the varied genomic mechanisms underlying this occurrence, and nominate KLF5 as a putative target for therapeutic intervention in cancer.
.
The evolution and diversification of ancient megathermal angiosperm lineages with Africa-India origins in Asian tropical forests is poorly understood because of the lack of reliable fossils. Our ...palaeobiogeographical analysis of pollen fossils from Africa and India combined with molecular data and fossil amber records suggest a tropical-African origin of Dipterocarpaceae during the mid-Cretaceous and its dispersal to India during the Late Maastrichtian and Paleocene, leading to range expansion of aseasonal dipterocarps on the Indian Plate. The India-Asia collision further facilitated the dispersal of dipterocarps from India to similar climatic zones in Southeast Asia, which supports their out-of-India migration. The dispersal pathway suggested for Dipterocarpaceae may provide a framework for an alternative biogeographic hypothesis for several megathermal angiosperm families that are presently widely distributed in Southeast Asia.
1. We conducted a field experiment to test whether aggregated spatial distributions were related to soil variation in locally sympatric tree species in the rain forests of Sarawak, Malaysia. ...Dryobalanops aromatica, Shorea laxa, and Swintonia schwenkii are naturally aggregated on low-fertility humult ultisols, Dryobalanops lanceolata and Hopea dryobalanoides on moderate-fertility udult ultisols and Shorea balanocarpoides is found on both soil types. 2. Seedlings of all six species were grown in a nested-factorial experiment for 20 months in humult and udult soils in gaps and in the understorey to test for soil-specific differences in performance. Phosphorus addition was used to test for effects due to P-limitation. 3. Four species showed significantly higher growth on their natural soils, but one humult-soil species (D. aromatica) and the broadly distributed species were not significantly affected by soil type. 4. One udult-soil species, D. lanceolata, had both lower relative growth rate and lower mycorrhizal colonization on humult soil. However, humult soils also had lower levels of Ca, Mg, K, N and probably water availability. 5. The overall ranking of growth rates among species was similar on the two soils. Growth rates were strongly positively correlated with leaf area ratio and specific leaf area among species in both soils. With the exception of D. aromatica, species of the higher-nutrient soils had higher growth rates on both soils. 6. Although P addition led to elevated soil-P concentrations, elevated root- and leaf-tissue P concentrations on both soils, there was no significant growth enhancement and therefore no evidence that P availability limits the growth or constrains the distribution of any of the six species in the field. Differences in soil water availability between soils may be more important. 7. Our results suggest that habitat-mediated differences in seedling performance strongly influence the spatial distributions of tropical trees and are therefore likely to play a key role in structuring tropical rain forest communities.
We combined two existing datasets of vegetation aboveground biomass (AGB) (Proceedings of the National Academy of Sciences of the United States of America, 108, 2011, 9899; Nature Climate Change, 2, ...2012, 182) into a pan‐tropical AGB map at 1‐km resolution using an independent reference dataset of field observations and locally calibrated high‐resolution biomass maps, harmonized and upscaled to 14 477 1‐km AGB estimates. Our data fusion approach uses bias removal and weighted linear averaging that incorporates and spatializes the biomass patterns indicated by the reference data. The method was applied independently in areas (strata) with homogeneous error patterns of the input (Saatchi and Baccini) maps, which were estimated from the reference data and additional covariates. Based on the fused map, we estimated AGB stock for the tropics (23.4 N–23.4 S) of 375 Pg dry mass, 9–18% lower than the Saatchi and Baccini estimates. The fused map also showed differing spatial patterns of AGB over large areas, with higher AGB density in the dense forest areas in the Congo basin, Eastern Amazon and South‐East Asia, and lower values in Central America and in most dry vegetation areas of Africa than either of the input maps. The validation exercise, based on 2118 estimates from the reference dataset not used in the fusion process, showed that the fused map had a RMSE 15–21% lower than that of the input maps and, most importantly, nearly unbiased estimates (mean bias 5 Mg dry mass ha⁻¹ vs. 21 and 28 Mg ha⁻¹ for the input maps). The fusion method can be applied at any scale including the policy‐relevant national level, where it can provide improved biomass estimates by integrating existing regional biomass maps as input maps and additional, country‐specific reference datasets.
Sarcopenia and exercise intolerance are major contributors to reduced quality of life in the elderly for which there are few effective treatments. We tested whether enhancing mitochondrial function ...and reducing mitochondrial oxidant production with SS-31 (elamipretide) could restore redox balance and improve skeletal muscle function in aged mice. Young (5 mo) and aged (26 mo) female C57BL/6Nia mice were treated for 8-weeks with 3 mg/kg/day SS-31. Mitochondrial function was assessed in vivo using 31P and optical spectroscopy. SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O). Despite the increased in vivo mitochondrial capacity, mitochondrial protein expression was either unchanged or reduced in the treated aged mice and respiration in permeabilized gastrocnemius (GAS) fibers was not different between the aged and aged+SS-31 mice. Treatment with SS-31 also restored redox homeostasis in the aged skeletal muscle. The glutathione redox status was more reduced and thiol redox proteomics indicated a robust reversal of cysteine S-glutathionylation post-translational modifications across the skeletal muscle proteome. The gastrocnemius in the age+SS-31 mice was more fatigue resistant with significantly greater mass compared to aged controls. This contributed to a significant increase in treadmill endurance compared to both pretreatment and untreated control values. These results demonstrate that the shift of redox homeostasis due to mitochondrial oxidant production in aged muscle is a key factor in energetic defects and exercise intolerance. Treatment with SS-31 restores redox homeostasis, improves mitochondrial quality, and increases exercise tolerance without an increase in mitochondrial content. Since elamipretide is currently in clinical trials these results indicate it may have direct translational value for improving exercise tolerance and quality of life in the elderly.
Display omitted
Phylogenetic relationships within tribe Shoreeae, containing the main elements of tropical forests in Southeast Asia, present a long-standing problem in the systematics of Dipterocarpaceae. ...Sequencing whole plastomes using next-generation sequencing- (NGS) based genome skimming is increasingly employed for investigating phylogenetic relationships of plants. Here, the usefulness of complete plastid genome sequences in resolving phylogenetic relationships within Shoreeae is evaluated.
A pipeline to obtain alignments of whole plastid genome sequences across individuals with different amounts of available data is presented. In total, 48 individuals, representing 37 species and four genera of the ecologically and economically important tribe Shoreeae sensu Ashton, were investigated. Phylogenetic trees were reconstructed using maximum parsimony, maximum likelihood and Bayesian inference.
Here, the first fully sequenced plastid genomes for the tribe Shoreeae are presented. Their size, GC content and gene order are comparable with those of other members of Malvales. Phylogenomic analyses demonstrate that whole plastid genomes are useful for inferring phylogenetic relationships among genera and groups of Shorea (Shoreeae) but fail to provide well-supported phylogenetic relationships among some of the most closely related species. Discordance in placement of Parashorea was observed between phylogenetic trees obtained from plastome analyses and those obtained from nuclear single nucleotide polymorphism (SNP) data sets identified in restriction-site associated sequencing (RADseq).
Phylogenomic analyses of the entire plastid genomes are useful for inferring phylogenetic relationships at lower taxonomic levels, but are not sufficient for detailed phylogenetic reconstructions of closely related species groups in Shoreeae. Discordance in placement of Parashorea was further investigated for evidence of ancient hybridization.
The response of tropical forests to global climate variability and change remains poorly understood. Results from long-term studies of permanent forest plots have reported different, and in some ...cases opposing trends in tropical forest dynamics. In this study, we examined changes in tree growth rates at four long-term permanent tropical forest research plots in relation to variation in solar radiation, temperature and precipitation. Temporal variation in the stand-level growth rates measured at five-year intervals was found to be positively correlated with variation in incoming solar radiation and negatively related to temporal variation in night-time temperatures. Taken alone, neither solar radiation variability nor the effects of night-time temperatures can account for the observed temporal variation in tree growth rates across sites, but when considered together, these two climate variables account for most of the observed temporal variability in tree growth rates. Further analysis indicates that the stand-level response is primarily driven by the responses of smaller-sized trees (less than 20 cm in diameter). The combined temperature and radiation responses identified in this study provide a potential explanation for the conflicting patterns in tree growth rates found in previous studies.
Decline in mean temperature with elevation correlates with a more or less gradual change in forest floristics mediated by minimum temperature tolerances and competition, and in its diversity, well ...documented on wet equatorial mountains. On the mountains of monsoon tropical Asia, the predominance of a single wet and dry season offers opportunity to relate increasing cloud and rainfall seasonality with a departure in a zonation most clearly recognised on equatorial mountains. Observations indicate that the lowland to lower montane forest transition is gradual and constant in elevation throughout the monsoon tropical Asia region, and contrasts with the variable elevation at which forest structure and physiognomy, alternatively floristics alone, changes between lower and upper equatorial montane forests. Both ecotones are observed to correlate with the elevation and seasonality at which decline in temperature daily results in condensation of water vapour into cloud, resulting in cloud shadow, and fog therefore water supply where cloud penetrates the canopy. Seasonal variation in these climatic interactions influence forest structure and physiognomy and, by mediating the interaction between vegetation and substrate, also leads to zonation in soils and consequently floristics. Historical biogeographical factors also influence zonal floristics.
PDF
