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Attenuating aberrant transcriptional circuits holds great promise for the treatment of numerous diseases, including cancer. However, development of transcriptional inhibitors is hampered by the lack of a generally accepted functional cellular readout to characterize their target specificity and on-target activity. We benchmarked the direct gene-regulatory signatures of six agents reported as inhibitors of the oncogenic transcription factor MYB against targeted MYB degradation in a nascent transcriptomics assay. The inhibitors demonstrated partial specificity for MYB target genes but displayed significant off-target activity. Unexpectedly, the inhibitors displayed bimodal on-target effects, acting as mixed agonists-antagonists. Our data uncover unforeseen agonist effects of small molecules originally developed as TF inhibitors and argue that rapid-kinetics benchmarking against degron models should be used for functional characterization of transcriptional modulators.Attenuating aberrant transcriptional circuits holds great promise for the treatment of numerous diseases, including cancer. However, development of transcriptional inhibitors is hampered by the lack of a generally accepted functional cellular readout to characterize their target specificity and on-target activity. We benchmarked the direct gene-regulatory signatures of six agents reported as inhibitors of the oncogenic transcription factor MYB against targeted MYB degradation in a nascent transcriptomics assay. The inhibitors demonstrated partial specificity for MYB target genes but displayed significant off-target activity. Unexpectedly, the inhibitors displayed bimodal on-target effects, acting as mixed agonists-antagonists. Our data uncover unforeseen agonist effects of small molecules originally developed as TF inhibitors and argue that rapid-kinetics benchmarking against degron models should be used for functional characterization of transcriptional modulators.

Lineage-defining transcription factors form densely interconnected circuits in chromatin occupancy assays, but the functional significance of these networks remains underexplored. We reconstructed the functional topology of a leukemia cell transcription network from the direct gene-regulatory programs of eight core transcriptional regulators established in pre-steady state assays coupling targeted protein degradation with nascent transcriptomics. The core regulators displayed narrow, largely non-overlapping direct transcriptional programs, forming a sparsely interconnected functional hierarchy stabilized by incoherent feed-forward loops. BET bromodomain and CDK7 inhibitors disrupted the core regulators' direct programs, acting as mixed agonists/antagonists. The network is predictive of dynamic gene expression behaviors in time-resolved assays and clinically relevant pathway activity in patient populations.

Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation (alloSCT) has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHC-II) proteins through unknown mechanisms. We developed CORENODE, a computational algorithm for genome-wide transcription network decomposition, that identified the transcription factors (TFs) IRF8 and MEF2C as positive regulators and MYB and MEIS1 as negative regulators of MHC-II expression in AML cells. We show that reduced MHC-II expression at relapse is transcriptionally driven by combinatorial changes in the levels of these TFs, acting both independently and through the MHC-II coactivator CIITA. Beyond the MHC-II genes, MYB and IRF8 antagonistically regulate a broad genetic program responsible for cytokine signaling and T-cell stimulation that displays reduced expression at relapse. A small number of cells with altered TF levels and silenced MHC-II expression are present at the time of initial leukemia diagnosis, likely contributing to eventual relapse. Our findings reveal an adaptive transcriptional mechanism of AML evolution after allogenic transplantation whereby combinatorial fluctuations of TF levels under immune pressure result in selection of cells with a silenced T-cell stimulation program. Competing Interest Statement KS has consulted for KronosBio and Auron Therapeutics, has stock options with Auron Therapeutics, and received grant funding from Novartis on topics unrelated to this manuscript. NVD is a current employee of Genentech, Inc., a member of the Roche Group. KE has consulted for Third Rock Ventures on topics unrelated to this manuscript. The other authors have no competing interests to report.

A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer. Competing Interest Statement K. Stegmaier has funding from Novartis Institute of Biomedical Research, consults for and has stock options in Auron Therapeutics, and has consulted for Kronos Bio and AstraZeneca on topics unrelated to this work. N.V. Dharia is a current employee of Genentech, Inc., a member of the Roche Group. J. Xavier Ferrucio is a current employee of Vor Biopharma. C.Y. Lin is a current employee of Kronos Bio. B. Nabet is an inventor on patent applications related to the dTAG system (WO/2017/024318, WO/2017/024319, WO/2018/148440, WO/2018/148443 and WO/2020/146250). K. Eagle has consulted for Third Rock Ventures and Flare Therapeutics on topics unrelated to this manuscript. All other authors declare no potential conflict of interest.

Abstract Rationale Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease. Objectives In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. Methods During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events. Measurements and Main Results The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. −25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation. Conclusions Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).

Farmers, food supply-chain entities, and policymakers need a simple but robust indicator to demonstrate progress toward reducing nitrogen pollution associated with food production. We show that nitrogen balance—the difference between nitrogen inputs and nitrogen outputs in an agricultural production system—is a robust measure of nitrogen losses that is simple to calculate, easily understood, and based on readily available farm data. Nitrogen balance provides farmers with a means of demonstrating to an increasingly concerned public that they are succeeding in reducing nitrogen losses while also improving the overall sustainability of their farming operation. Likewise, supply-chain companies and policymakers can use nitrogen balance to track progress toward sustainability goals. We describe the value of nitrogen balance in translating environmental targets into actionable goals for farmers and illustrate the potential roles of science, policy, and agricultural support networks in helping farmers achieve them.

Tropical mangrove forests have been described as “coastal kidneys,” promoting sediment deposition and filtering contaminants, including excess nutrients. Coastal areas throughout the world are experiencing increased human activities, resulting in altered geomorphology, hydrology, and nutrient inputs. To effectively manage and sustain coastal mangroves, it is important to understand nitrogen (N) storage and accumulation in systems where human activities are causing rapid changes in N inputs and cycling. We examined N storage and accumulation rates in recent (1970 – 2016) and historic (1930 – 1970) decades in the context of urbanization in the San Juan Bay Estuary (SJBE, Puerto Rico), using mangrove soil cores that were radiometrically dated. Local anthropogenic stressors can alter N storage rates in peri-urban mangrove systems either directly by increasing N soil fertility or indirectly by altering hydrology (e.g., dredging, filling, and canalization). Nitrogen accumulation rates were greater in recent decades than historic decades at Piñones Forest and Martin Peña East. Martin Peña East was characterized by high urbanization, and Piñones, by the least urbanization in the SJBE. The mangrove forest at Martin Peña East fringed a poorly drained canal and often received raw sewage inputs, with N accumulation rates ranging from 17.7 to 37.9 g m –2 y –1 in recent decades. The Piñones Forest was isolated and had low flushing, possibly exacerbated by river damming, with N accumulation rates ranging from 18.6 to 24.2 g m –2 y –1 in recent decades. Nearly all (96.3%) of the estuary-wide mangrove N (9.4 Mg ha –1 ) was stored in the soils with 7.1 Mg ha –1 sequestered during 1970–2017 (0–18 cm) and 2.3 Mg ha –1 during 1930–1970 (19–28 cm). Estuary-wide mangrove soil N accumulation rates were over twice as great in recent decades (0.18 ± 0.002 Mg ha –1 y –1 ) than historically (0.08 ± 0.001 Mg ha –1 y –1 ). Nitrogen accumulation rates in SJBE mangrove soils in recent times were twofold larger than the rate of human-consumed food N that is exported as wastewater (0.08 Mg ha –1 y –1 ), suggesting the potential for mangroves to sequester human-derived N. Conservation and effective management of mangrove forests and their surrounding watersheds in the Anthropocene are important for maintaining water quality in coastal communities throughout tropical regions.

Mangroves sequester significant quantities of organic carbon (C) because of high rates of burial in the soil and storage in biomass. We estimated mangrove forest C storage and accumulation rates in aboveground and belowground components among five sites along an urbanization gradient in the San Juan Bay Estuary, Puerto Rico. Sites included the highly urbanized and clogged Caño Martin Peña in the western half of the estuary, a series of lagoons in the center of the estuary, and a tropical forest reserve (Piñones) in the easternmost part. Radiometrically dated cores were used to determine sediment accretion and soil C storage and burial rates. Measurements of tree dendrometers coupled with allometric equations were used to estimate aboveground biomass. Estuary-wide mangrove forest C storage and accumulation rates were estimated using interpolation methods and coastal vegetation cover data. In recent decades (1970–2016), the highly urbanized Martin Peña East (MPE) site with low flushing had the highest C storage and burial rates among sites. The MPE soil carbon burial rate was over twice as great as global estimates. Mangrove forest C burial rates in recent decades were significantly greater than historic decades (1930–1970) at Caño Martin Peña and Piñones. Although MPE and Piñones had similarly low flushing, the landscape settings (clogged canal vs forest reserve) and urbanization (high vs low) were different. Apparently, not only urbanization, but site-specific flushing patterns, landscape setting, and soil fertility affected soil C storage and burial rates. There was no difference in C burial rates between historic and recent decades at the San José and La Torrecilla lagoons. Mangrove forests had soil C burial rates ranging from 88 g m –2 y –1 at the San José lagoon to 469 g m –2 y –1 at the MPE in recent decades. Watershed anthropogenic CO 2 emissions (1.56 million Mg C y –1 ) far exceeded the annual mangrove forest C storage rates (aboveground biomass plus soils: 17,713 Mg C y –1 ). A combination of maintaining healthy mangrove forests and reducing anthropogenic emissions might be necessary to mitigate greenhouse gas emissions in urban, tropical areas.

Social networks can be organized into communities of closely connected nodes, a property known as modularity. Because diseases, information, and behaviors spread faster within communities than between communities, understanding modularity has broad implications for public policy, epidemiology and the social sciences. Explanations for community formation in social networks often incorporate the attributes of individual people, such as gender, ethnicity or shared activities. High modularity is also a property of large-scale social networks, where each node represents a population of individuals at a location, such as call flow between mobile phone towers. However, whether or not place-based attributes, including land cover and economic activity, can predict community membership for network nodes in large-scale networks remains unknown. We describe the pattern of modularity in a mobile phone communication network in the Dominican Republic, and use a linear discriminant analysis (LDA) to determine whether geographic context can explain community membership. Our results demonstrate that place-based attributes, including sugar cane production, urbanization, distance to the nearest airport, and wealth, correctly predicted community membership for over 70% of mobile phone towers. We observed a strongly positive correlation (r = 0.97) between the modularity score and the predictive ability of the LDA, suggesting that place-based attributes can accurately represent the processes driving modularity. In the absence of social network data, the methods we present can be used to predict community membership over large scales using solely place-based attributes.