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Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform-containing complex to the mutant TERT promoter. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM.

Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1-independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.

While forced labor in the world's fishing fleet has been widely documented, its extent remains unknown. No methods previously existed for remotely identifying individual fishing vessels potentially engaged in these abuses on a global scale. By combining expertise from human rights practitioners and satellite vessel monitoring data, we show that vessels reported to use forced labor behave in systematically different ways from other vessels. We exploit this insight by using machine learning to identify high-risk vessels from among 16,000 industrial longliner, squid jigger, and trawler fishing vessels. Our model reveals that between 14% and 26% of vessels were high-risk, and also reveals patterns of where these vessels fished and which ports they visited. Between 57,000 and 100,000 individuals worked on these vessels, many of whom may have been forced labor victims. This information provides unprecedented opportunities for novel interventions to combat this humanitarian tragedy. More broadly, this research demonstrates a proof of concept for using remote sensing to detect forced labor abuses.

Marine protected areas (MPAs) are conservation tools that are increasingly implemented, with growing national commitments for MPA expansion. Perhaps the greatest challenge to expanded use of MPAs is the perceived trade-off between protection and food production. Since MPAs can benefit both conservation and fisheries in areas experiencing overfishing and since overfishing is common in many coastal nations, we ask how MPAs can be designed specifically to improve fisheries yields. We assembled distribution, life history, and fisheries exploitation data for 1,338 commercially important stocks to derive an optimized network of MPAs globally. We show that strategically expanding the existing global MPA network to protect an additional 5% of the ocean could increase future catch by at least 20% via spillover, generating 9 to 12 million metric tons more food annually than in a business-as-usual world with no additional protection. Our results demonstrate how food provisioning can be a central driver of MPA design, offering a pathway to strategically conserve ocean areas while securing seafood for the future.

Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

Most large-scale conservation policies are anticipated or announced in advance. This risks the possibility of preemptive resource extraction before the conservation intervention goes into force. We use a high-resolution dataset of satellite-based fishing activity to show that anticipation of an impending no-take marine reserve undermines the policy by triggering an unintended race-to-fish. We study one of the world's largest marine reserves, the Phoenix Islands Protected Area (PIPA), and find that fishers more than doubled their fishing effort once this area was earmarked for eventual protected status. The additional fishing effort resulted in an impoverished starting point for PIPA equivalent to 1.5 y of banned fishing. Extrapolating this behavior globally, we estimate that if other marine reserve announcements were to trigger similar preemptive fishing, this could temporarily increase the share of overextracted fisheries from 65% to 72%. Our findings have implications for general conservation efforts as well as the methods that scientists use to monitor and evaluate policy efficacy.

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

Management of the diverse fisheries of the world has had mixed success. While managing single species in data-rich environments has been largely effective, perhaps the greatest challenge facing fishery managers is how to deal with mixed stocks of fish with a range of life histories that reside in the same location. Because many fishing gears are nonselective, and the costs of making gear selective can be high, a particular problem is bycatch of weak stocks. This problem is most severe when the weak stock is long-lived and has low fecundity and thus requires a very long recovery time once overfished. We investigate the role that marine reserves might play in solving this challenging and ubiquitous problem in ecosystem-based management. Evidence for marine reserves' potential to manage fisheries in an ecosystem context has been mixed, so we develop a heuristic strategic mathematical model to obtain general conclusions about the merits of managing multispecies fisheries by using reserves relative to managing them with nonspatial approaches. We show that for many fisheries, yields of strong stocks can be increased, and persistence of weak stocks can be ensured, by using marine reserves rather than by using traditional nonspatial approaches alone. Thus, reserves have a distinct advantage as a management tool in many of the most critical multispecies settings. We also show how the West Coast groundfish fishery of the United States meets these conditions, suggesting that management by reserves may be a superior option in that case.

Economic incentives to harvest a species usually diminish as its abundance declines, because harvest costs increase. This prevents harvesting to extinction. A known exception can occur if consumer demand causes a declining species' harvest price to rise faster than costs. This threat may affect rare and valuable species, such as large land mammals, sturgeons, and bluefin tunas. We analyze a similar but underappreciated threat, which arises when the geographic area (range) occupied by a species contracts as its abundance declines. Range contractions maintain the local densities of declining populations, which facilitates harvesting to extinction by preventing abundance declines from causing harvest costs to rise. Factors causing such range contractions include schooling, herding, or flocking behaviors-which, ironically, can be predator-avoidance adaptations; patchy environments; habitat loss; and climate change. We use a simple model to identify combinations of range contractions and price increases capable of causing extinction from profitable overharvesting, and we compare these to an empirical review. We find that some aquatic species that school or forage in patchy environments experience sufficiently severe range contractions as they decline to allow profitable harvesting to extinction even with little or no price increase; and some high-value declining aquatic species experience severe price increases. For terrestrial species, the data needed to evaluate our theory are scarce, but available evidence suggests that extinction-enabling range contractions may be common among declining mammals and birds. Thus, factors causing range contraction as abundance declines may pose unexpectedly large extinction risks to harvested species.

Indiscriminate and intense fishing has occurred in many marine ecosystems around the world. Although this practice may have negative effects on biodiversity and populations of individual species, it may also increase total fishery productivity by removing predatory fish. We examine the potential for this phenomenon to explain the high reported wild catches in the East China Sea-one of the most productive ecosystems in the world that has also had its catch reporting accuracy and fishery management questioned. We show that reported catches can be approximated using an ecosystem model that allows for trophic cascades (i.e., the depletion of predators and consequent increases in production of their prey). This would be the world's largest known example of marine ecosystem "engineering" and suggests that trade-offs between conservation and food production exist. We project that fishing practices could be modified to increase total catches, revenue, and biomass in the East China Sea, but single-species management would decrease both catches and revenue by reversing the trophic cascades. Our results suggest that implementing single-species management in currently lightly managed and highly exploited multispecies fisheries (which account for a large fraction of global fish catch) may result in decreases in global catch. Efforts to reform management in these fisheries will need to consider system wide impacts of changes in management, rather than focusing only on individual species.

Data from 4,713 fisheries worldwide, representing 78% of global reported fish catch, are analyzed to estimate the status, trends, and benefits of alternative approaches to recovering depleted fisheries. For each fishery, we estimate current biological status and forecast the impacts of contrasting management regimes on catch, profit, and biomass of fish in the sea. We estimate unique recovery targets and trajectories for each fishery, calculate the year-by-year effects of alternative recovery approaches, and model how alternative institutional reforms affect recovery outcomes. Current status is highly heterogeneous-the median fishery is in poor health (overfished, with further overfishing occurring), although 32% of fisheries are in good biological, although not necessarily economic, condition. Our business-as-usual scenario projects further divergence and continued collapse for many of the world's fisheries. Applying sound management reforms to global fisheries in our dataset could generate annual increases exceeding 16 million metric tons (MMT) in catch, $53 billion in profit, and 619 MMT in biomass relative to business as usual. We also find that, with appropriate reforms, recovery can happen quickly, with the median fishery taking under 10 y to reach recovery targets. Our results show that commonsense reforms to fishery management would dramatically improve overall fish abundance while increasing food security and profits.

The expansion of marine protected areas (MPAs) is a core focus of global conservation efforts, with the "30x30" initiative to protect 30% of the ocean by 2030 serving as a prominent example of this trend. We consider a series of proposed MPA network expansions of various sizes, and we forecast the impact this increase in protection would have on global patterns of fishing effort. We do so by building a predictive machine learning model trained on a global dataset of satellite-based fishing vessel monitoring data, current MPA locations, and spatiotemporal environmental, geographic, political, and economic features. We then use this model to predict future fishing effort under various MPA expansion scenarios compared to a business-as-usual counterfactual scenario that includes no new MPAs. The difference between these scenarios represents the predicted change in fishing effort associated with MPA expansion. We find that regardless of the MPA network objectives or size, fishing effort would decrease inside the MPAs, though by much less than 100%. Moreover, we find that the reduction in fishing effort inside MPAs does not simply redistribute outside--rather, fishing effort outside MPAs would also decline. The overall magnitude of the predicted decrease in global fishing effort principally depends on where networks are placed in relation to existing fishing effort. MPA expansion will lead to a global redistribution of fishing effort that should be accounted for in network design, implementation, and impact evaluation. [ABSTRACT FROM AUTHOR]

We investigate how host mucus glycan composition interacts with dietary carbohydrate content to influence the composition and expressed functions of a human gut community. The humanized gnotobiotic mice mimic humans with a nonsecretor phenotype due to knockout of their α1-2 fucosyltransferase (Fut2) gene. The fecal microbiota of Fut2(-) mice that lack fucosylated host glycans show decreased alpha diversity relative to Fut2(+) mice and exhibit significant differences in community composition. A glucose-rich plant polysaccharide-deficient (PD) diet exerted a strong effect on the microbiota membership but eliminated the effect of Fut2 genotype. Additionally fecal metabolites predicted host genotype in mice on a polysaccharide-rich standard diet but not on a PD diet. A more detailed mechanistic analysis of these interactions involved colonization of gnotobiotic Fut2(+) and Fut2(-) mice with Bacteroides thetaiotaomicron, a prominent member of the human gut microbiota known to adaptively forage host mucosal glycans when dietary polysaccharides are absent. Within Fut2(-) mice, the B. thetaiotaomicron fucose catabolic pathway was markedly down-regulated, whereas BT4241-4247, an operon responsive to terminal β-galactose, the precursor that accumulates in the Fut2(-) mice, was significantly up-regulated. These changes in B. thetaiotaomicron gene expression were only evident in mice fed a PD diet, wherein B. thetaiotaomicron relies on host mucus consumption. Furthermore, up-regulation of the BT4241-4247 operon was also seen in humanized Fut2(-) mice. Together, these data demonstrate that differences in host genotype that affect the carbohydrate landscape of the distal gut interact with diet to alter the composition and function of resident microbes in a diet-dependent manner.

Alternative splicing (AS) allows increased diversity and orthogonal regulation of the transcriptional products of mammalian genomes. To assess the distribution and variation of alternative splicing across cell lineages of the immune system, we comprehensively analyzed RNA sequencing and microarray data generated by the Immunological Genome Project Consortium. AS is pervasive: 60% of genes showed frequent AS isoforms in T or B lymphocytes, with 7,599 previously unreported isoforms. Distinct cell specificity was observed, with differential exon skipping in 5% of genes otherwise coexpressed in both B and T cells. The distribution of isoforms was mostly all or none, suggesting on/off switching as a frequent mode of AS regulation in lymphocytes. From the identification of differential exon use in the microarray data, clustering of exon inclusion/exclusion patterns across all Immunological Genome Project cell types showed that ∼70% of AS exons are distributed along a common pattern linked to lineage differentiation and cell cycling. Other AS events distinguished myeloid from lymphoid cells or affected only a small set of exons without clear lineage specificity (e.g., Ptprc). Computational analysis predicted specific associations between AS exons and splicing regulators, which were verified by detection of the hnRPLL/Ptprc connection.

A commentary published in the Proceedings of the National Academy of Sciences challenges the belief that Marine Protected Areas (MPAs) displace fisheries. The study found that fishing effort actually decreases in and around MPAs, suggesting a recovery of fish stocks. The article also addresses misconceptions about MPAs, such as the idea that recreational fishing is less harmful to biodiversity and that only commercial fishing should be excluded from MPAs. The study concludes that more fully protected MPAs will benefit fisheries. The article also discusses the benefits and challenges of establishing fully protected MPAs, arguing that the costs are relatively low and that a global network of fully protected MPAs is needed. [Extracted from the article]

Many nearshore fish and invertebrate populations are overexploited even when apparently coherent management structures are in place. One potential cause of mismanagement may be a poor understanding and accounting of stochasticity, particularly for stock recruitment. Many of the fishes and invertebrates that comprise nearshore fisheries are relatively sedentary as adults but have an obligate larval pelagic stage that is dispersed by ocean currents. Here, we demonstrate that larval connectivity is inherently an intermittent and heterogeneous process on annual time scales. This stochasticity arises from the advection of pelagic larvae by chaotic coastal circulations. This result departs from typical assumptions where larvae simply diffuse from one site to another or where complex connectivity patterns are created by transport within spatially complicated environments. We derive a statistical model for the expected variability in larval settlement patterns and demonstrate how larval connectivity varies as a function of different biological and physical processes. The stochastic nature of larval connectivity creates an unavoidable uncertainty in the assessment of fish recruitment and the resulting forecasts of sustainable yields.