Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, ...using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.
•BET inhibition exhibits antitumor efficacy in vitro and in vivo•BRD4 localizes in an asymmetric manner to massively overloaded enhancer regions•Genes with adjacent BRD4-loaded super-enhancers are sensitive to BET inhibition•Cancer dependencies are found among super-enhancer-marked genes
Numerous international legal regimes now seek to address the global depletion of fish stocks, and increasingly their activities overlap. The relevant laws were developed at different times by ...different groups of states. They are motivated by divergent economic approaches, influenced by disparate non-state actors, and implemented by separate institutions such as the World Trade Organization and the United Nations Food and Agriculture Organization. Margaret Young shows how these and other factors affect the interaction between regimes. Her empirical and doctrinal analysis moves beyond the discussion of conflicting norms that has dominated the fragmentation debate. Case-studies include the negotiation of new rules on fisheries subsidies, the restriction of trade in endangered marine species and the adjudication of fisheries import bans. She explores how regimes should interact, in fisheries governance and beyond, to offer insights into the practice and legitimacy of regime interaction in international law.
Growth and differentiation factor 15 (GDF15) is an inflammation-associated hormone with poorly defined biology. Here, we investigated the role of GDF15 in bacterial and viral infections. We found ...that inflammation induced GDF15, and that GDF15 was necessary for surviving both bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen control or the magnitude of inflammatory response, suggesting a role in disease tolerance. Indeed, we found that GDF15 was required for hepatic sympathetic outflow and triglyceride metabolism. Failure to defend the lower limit of plasma triglyceride levels was associated with impaired cardiac function and maintenance of body temperature, effects that could be rescued by exogenous administration of lipids. Together, we show that GDF15 coordinates tolerance to inflammatory damage through regulation of triglyceride metabolism.
Display omitted
•GDF15 is induced upon bacterial and viral inflammation•GDF15 promotes metabolic adaptation to systemic inflammation•GDF15 stimulates hepatic triglyceride export via beta-adrenergic signaling•Maintenance of triglyceride levels during acute inflammation is cardioprotective
The hormone GDF15 promotes tolerance and survival during conditions of infection and sepsis by modulating systemic levels of plasma triglycerides.
Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 ...within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ∼80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.
•AML cases with DNMT3A mutations at R882 exhibit focal hypomethylation•R882H DNMT3A is a dominant-negative inhibitor of WT DNMT3A•WT DNMT3A forms stable, active homotetramers•R882H DNMT3A dominantly disrupts DNMT3A tetramerization
Heterozygous DNMT3A R882H mutation is common in acute myeloid leukemia (AML). Russler-Germain et al. show that DNMT3AR882H inhibits wild-type DNMT3A activity in cells, but not in vitro, and that AML cells with the R882H mutation have reduced de novo methyltransferase activity and focal CpG hypomethylation.
Phytoplankton production drives marine ecosystem trophic-structure and global fisheries yields. Phytoplankton biomass is particularly influential near coral reef islands and atolls that span the ...oligotrophic tropical oceans. The paradoxical enhancement in phytoplankton near an island-reef ecosystem--Island Mass Effect (IME)--was first documented 60 years ago, yet much remains unknown about the prevalence and drivers of this ecologically important phenomenon. Here we provide the first basin-scale investigation of IME. We show that IME is a near-ubiquitous feature among a majority (91%) of coral reef ecosystems surveyed, creating near-island 'hotspots' of phytoplankton biomass throughout the upper water column. Variations in IME strength are governed by geomorphic type (atoll vs island), bathymetric slope, reef area and local human impacts (for example, human-derived nutrient input). These ocean oases increase nearshore phytoplankton biomass by up to 86% over oceanic conditions, providing basal energetic resources to higher trophic levels that support subsistence-based human populations.
The negotiation of the free trade agreement (FTA) between Australia and the United Kingdom promised to integrate trade and climate policies. As a leader of the United Nations Framework Convention on ...Climate Change (UNFCCC) conference in Glasgow, the UK seemed well-placed to exert pressure on Australia, a country that was yet to embrace a target of net zero emissions by 2050. This article asks whether the FTA achieves this aim. It explains the link between trade liberalisation and climate change, referring to the scale and composition of economic activity and drawing upon examples from energy, agriculture, building and transportation sectors, as well as strategic factors. It provides an original analytical framework to assess the FTA's contributions to climate change goals, pointing to: (1) provisions to strengthen climate commitments, including net zero targets; (2) provisions to facilitate trade and investment in climate-related areas; and (3) provisions relating to enforcement and cooperation. It compares selected initiatives of other FTAs, including the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP), the European Union–Canada Comprehensive Economic and Trade Agreement (CETA), the UK–New Zealand FTA and the Singapore–Australia Green Economy Agreement. It reviews the FTA's negotiating process and its aftermath, including complaints about public participation. The article's conclusion that the FTA makes minimal contribution to climate change mitigation has implications for the broader quest for mutually supportive trade and climate policies, and, now that a net zero target has been legislated by the newly elected Australian Parliament, for the FTA's future implementation.
The integrastatins, epicoccolide A and epicoccongirone A, are natural products containing a unique 6.6.6.6-tetracyclic core framework that exhibit a broad spectrum of biological activities. A ...synthesis of the common core of epicoccolide A and epicocconigrone A has been achieved using an umpolung alkylation–lactonization to assemble an isochromanone from which the bridged 1,3-dioxane was readily assembled. A different strategy was required to access the core on the integrastatins; an initial aryllithium addition to an aldehyde, followed by oxidation and treatment of the masked dihydroxyketone with acid gave the desired core structure.
In a small series of patients with refractory Hodgkin's lymphoma, a substantial rate of tumor regression (87%) was documented in response to blockade of the programmed death 1 pathway.
The programmed ...death 1 (PD-1) pathway serves as a checkpoint to limit T-cell–mediated immune responses.
1
Both PD-1 ligands, PD-L1 and PD-L2, engage the PD-1 receptor and induce PD-1 signaling and associated T-cell “exhaustion,” a reversible inhibition of T-cell activation and proliferation.
1
By expressing PD-1 ligands on the cell surface and engaging PD-1 receptor–positive immune effector cells, tumors can co-opt the PD-1 pathway to evade an immune response.
2
PD-1–blocking antibodies have been used to enhance immunity in solid tumors and obtain durable clinical responses with an acceptable safety profile.
2
–
5
Preliminary data also support empirical PD-1 blockade as a therapeutic strategy . . .
Measures to combat illegal, unreported and unregulated (IUU) fishing increasingly seek to constrain access to markets. These measures include enhanced seafood traceability and catch documentation ...schemes, the blocking of port access and landings, the identification and assessment of vessels engaged in IUU fishing and the prohibition on imports, transhipments or trade of fish products. It is important that such measures are in accordance with international law, including the agreements of the World Trade Organisation (WTO). This article evaluates a range of market-related measures for compatibility with international trade law, including the General Agreement on Tariffs and Trade (GATT) and the Agreement on Technical Barriers to Trade. The law requires measures to be non-discriminatory and, for certain technical regulations, not more trade-restrictive than necessary to achieve a legitimate objective. However, there are exceptions to these rules, including for measures relating to the conservation of exhaustible natural resources or for measures necessary for the protection of animal life or health, public morals, or to secure compliance with certain laws or regulations. While the design of current unilateral measures to combat IUU fishing appears to accord with trade law requirements, this article argues that there is scope for a wider and more collective approach. In this vein, new provisions in the recently concluded Trans-Pacific Partnership (TPP) are identified. The article concludes with recommendations for governments, international organisations, private actors and the global community wishing to take action in this area.
•Catch documents, traceability measures and import bans should be non-discriminatory.•As technical regulations, measures should not be unnecessary obstacles to trade.•There is scope for a more collective approach to market-based measures.•Consensus can be developed in regional and multilateral trade and fisheries forums.•The Trans-Pacific Partnership (TPP) signals that measures are likely to be compatible.
To assess the genetic consequences of induced pluripotent stem cell (iPSC) reprogramming, we sequenced the genomes of ten murine iPSC clones derived from three independent reprogramming experiments, ...and compared them to their parental cell genomes. We detected hundreds of single nucleotide variants (SNVs) in every clone, with an average of 11 in coding regions. In two experiments, all SNVs were unique for each clone and did not cluster in pathways, but in the third, all four iPSC clones contained 157 shared genetic variants, which could also be detected in rare cells (<1 in 500) within the parental MEF pool. These data suggest that most of the genetic variation in iPSC clones is not caused by reprogramming per se, but is rather a consequence of cloning individual cells, which “captures” their mutational history. These findings have implications for the development and therapeutic use of cells that are reprogrammed by any method.
► iPSC clones contain hundreds of SNVs that are unique to each clone ► Most iPSC genomes do not contain recurrently mutated genes or pathways ► Reprogramming can select for rare cells with shared genetic variants ► Most SNVs are probably preexisting mutations “captured” by cloning
PDF
