1. Planning for nature conservation has increasingly emphasised the concepts of resilience and spatial networks. Although the importance of habitat networks for individual species is clear, their ...significance for long-term ecological resilience and multi-species conservation strategies is less established. 2. Referencing spatial network theory, we describe the conceptual basis for defining and assessing a network of wildlife areas that supports species' resilience to multiple forms of perturbations and pressures. We explore actions that could enhance network resilience at a range of scales, based on ecological principles, with reference to four well-established strategies for intervention in a spatial network ("Better, Bigger, More and Joined") from the influential Making Space for Nature report by Lawton et al. (2010). 3. Building existing theory into useable and scalable approaches applicable to large numbers of species is challenging but tractable. We illustrate the policy context, describe the elements of a long-term adaptive management plan and provide example actions, metrics and targets for early implementation using England as a case study, where there is an opportunity to include large-scale ecological planning in a newly launched 25-year environment plan. 4. Policy implications. The concept of resilient ecological networks has attracted sc entific and political support, but there is no consensus on what a resilient network would look like, or how to assess it. Therefore, it is unclear whether existing targets for action will be sufficient to achieve network resilience. We show that the scientific principles to place resilience and network theory at the heart of largescale and long-term environmental planning are established and ready to implement in practice. Delivering a resilient network to support nature recovery is achievable and can be integrated with ongoing conservation actions and targets, by assessing their effectiveness on properties of the entire network. England's 25 Year Environment Plan promises to deliver a natural environment that is protected and enhanced for the future and so provides the ideal testbed.
Host genetic factors can confer resistance against malaria
, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between ...candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member
PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.
: Although thousands of clinical isolates of
are being sequenced and analysed by short read technology, the data do not resolve the highly variable subtelomeric regions of the genomes that contain ...polymorphic gene families involved in immune evasion and pathogenesis. There is also no current standard definition of the boundaries of these variable subtelomeric regions.
: Using long-read sequence data (Pacific Biosciences SMRT technology), we assembled and annotated the genomes of 15
isolates, ten of which are newly cultured clinical isolates. We performed comparative analysis of the entire genome with particular emphasis on the subtelomeric regions and the internal
genes clusters.
: The nearly complete sequence of these 15 isolates has enabled us to define a highly conserved core genome, to delineate the boundaries of the subtelomeric regions, and to compare these across isolates. We found highly structured variable regions in the genome. Some exported gene families purportedly involved in release of merozoites show copy number variation. As an example of ongoing genome evolution, we found a novel CLAG gene in six isolates. We also found a novel gene that was relatively enriched in the South East Asian isolates compared to those from Africa.
: These 15 manually curated new reference genome sequences with their nearly complete subtelomeric regions and fully assembled genes are an important new resource for the malaria research community. We report the overall conserved structure and pattern of important gene families and the more clearly defined subtelomeric regions.
In mammals, the mechanisms regulating the number of active copies of the ~200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the ...transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1-induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation.
Elevated ribosome biogenesis in oncogene‐driven cancers is commonly targeted by DNA‐damaging cytotoxic drugs. Our previous first‐in‐human trial of CX‐5461, a novel, less genotoxic agent that ...specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single‐agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX‐5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP‐dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I‐directed therapies.
Synopsis
Specific inhibition of rRNA synthesis has been reported as an effective new treatment for refractory blood cancer, but patients relapse. Here, the development of resistance is shown to depend on reprogrammed mRNA translation and subsequent upregulation of a metabolism‐dependent survival pathway.
The efficacy of acute, combinatorial ribosome‐targeting therapy in vivo is associated with downregulation of the cells’ translational activity and energy metabolism
Therapeutic resistance is mediated by translational alterations that promote elevated metabolic activity and activate a cAMP‐dependent pro‐survival mechanism
The induced pro‐survival mechanism acts via EPAC1/2 and is targetable by metformin in vitro and in vivo
The identified metabolic vulnerability of ribosome‐targeting therapy resistance can be exploited to improve treatment efficacy in hematological cancers including lymphoma and acute myeloid leukemia.
The elevated metabolic activity and activation of cAMP‐dependent pro‐survival mechanisms that lead to resistance of hematological cancers towards rRNA synthesis inhibition also poses a potentially targetable vulnerability.
Aim: Climate change threatens biodiversity in all ecosystems, and major shifts in species distributions are expected. Freshwater ecosystems are considered particularly vulnerable due to the ...ectothermic physiology of most freshwater species and their limited habitat extent and capacity to track climate trends. In this study, we examined what broad patterns in freshwater riverine species turnover might be expected under climate change across continental Australia and what are the implications of these patterns for aquatic species and the low aquatic biodiversity of some bioregions? Location: Continental Australia. Methods: We built statistical relationships between bioclimatic environments and the occurrence of species of four freshwater taxa (freshwater fish, crayfish, turtles and frogs) and examined trends in projected species turnover for a ' business as usual' climate scenario. We used Maxent to model species distributions and present the median projection across 18 global climate models. A recently derived national stream network was used to generate estimates of mean annual river flow and to produce realistic species distributions and migration options by restricting dispersal and migration opportunities usually available to riverine fauna. Results: High species turnover was driven overwhelmingly by potential local extinctions particularly for stream frogs and crayfish where their current biodiversity is largely confined to higher elevation headwater streams. We predicted high turnover for inland regions of Australia, which are arid and generally support fewer freshwater species. Main conclusions: Our analysis indicates that under the most severe emissions pathway, projected climate change is likely to cause substantial changes to the composition of faunal assemblages in Australian rivers well before the end of this century. While freshwater systems globally are subject to immediate and pressing threats from anthropogenic land and water use, management interventions addressing these pressures need to be considered within the context of climate change.
MYC-driven B-cell lymphomas are addicted to increased levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi ...suppresses lymphomagenesis by decreasing translational capacity and/or by p53 activation mediated by the impaired RiBi checkpoint (IRBC). Here we generated Eμ-Myc lymphoma cells expressing inducible short hairpin RNAs to either ribosomal protein L7a (RPL7a) or RPL11, the latter an essential component of the IRBC. The loss of either protein reduced RiBi, protein synthesis, and cell proliferation to similar extents. However, only RPL7a depletion induced p53-mediated apoptosis through the selective proteasomal degradation of antiapoptotic MCL-1, indicating the critical role of the IRBC in this mechanism. Strikingly, low concentrations of the US Food and Drug Administration-approved anticancer RNA polymerase I inhibitor Actinomycin D (ActD) dramatically prolonged the survival of mice harboring Trp53+/+;Eμ-Myc but not Trp53-/-;Eμ-Myc lymphomas, which provides a rationale for treating MYC-driven B-cell lymphomas with ActD. Importantly, the molecular effects of ActD on Eμ-Myc cells were recapitulated in human B-cell lymphoma cell lines, highlighting the potential for ActD as a therapeutic avenue for p53 wild-type lymphoma.
The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate ...pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.
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Identification of critical genes regulating p53 via nucleolar surveillance pathway (NSP)
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When disrupted, genes associated with ribosome biogenesis most potently stabilize p53
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A functional NSP is essential for all nuclear-acting stresses to stabilize p53
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The NSP ensures that ribosome biogenesis is synchronized with cellular proliferation
Hannan et al. utilize genome-wide functional screening approaches to identify genes and pathways that, when perturbed, modulate p53 under ribosomal stress, including HEATR3. Their findings demonstrate that the nucleolar surveillance pathway is a primary integrator of all nuclear-acting stresses that stabilize p53.
In the setting of world population growth and migration, global health issues have an increasing impact on domestic conditions and our medical practitioners. The authors ask: What exactly constitutes ...global health, and how much do U.S. and Canadian medical students or practitioners need to know about it? To address this topic, the authors convened an American Society for Tropical Medicine and Hygiene Committee on Medical Education, sought input from the Global Health Education Consortium, and surveyed members of the American Committee on Clinical Tropical Medicine and Travelers' Health for educational priorities within the tropical medicine field. The information gained from these sources has been distilled into three domains of global health competency that the authors propose each medical school curriculum should try to achieve for all students: global burden of disease, traveler's medicine, and immigrant health. The authors present here the rationale for altering curricula to include these three topics as a starting point for discussion among medical educators.
Given the globally poor protection of fresh waters for their intrinsic ecological values, assessments are needed to determine how well fresh waters and supported fish species are incidentally ...protected within existing terrestrial protected-area networks, and to identify their vulnerability to human-induced disturbances. To date, gaps in data have severely constrained any attempt to explore the representation of fresh waters in tropical regions.
We determined the distribution of fresh waters and fish diversity in the Wet Tropics of Queensland, Australia. We then used distribution data of fresh waters, fish species, human-induced disturbances, and the terrestrial protected-area network to assess the effectiveness of terrestrial protected areas for fresh waters and fish species. We also identified human-induced disturbances likely to influence the effectiveness of freshwater protection and evaluated the vulnerability of fresh waters to these disturbances within and outside protected areas. The representation of fresh waters and fish species in the protected areas of the Wet Tropics is poor: 83% of stream types defined by order, 75% of wetland types, and 89% of fish species have less than 20% of their total Wet Tropics length, area or distribution completely within IUCN category II protected areas. Numerous disturbances affect fresh waters both within and outside of protected areas despite the high level of protection afforded to terrestrial areas in the Wet Tropics (>60% of the region). High-order streams and associated wetlands are influenced by the greatest number of human-induced disturbances and are also the least protected. Thirty-two percent of stream length upstream of protected areas has at least one human-induced disturbance present.
We demonstrate the need for greater consideration of explicit protection and off-reserve management for fresh waters and supported biodiversity by showing that, even in a region where terrestrial protection is high, it does not adequately capture fresh waters.
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