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Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1–Menin and MLL3/4–UTX chromatin-modifying complexes that dictates response to Menin–MLL inhibitors. MLL1–Menin safeguards leukemia survival by impeding the binding of the MLL3/4–UTX complex at a subset of target gene promoters. Disrupting the Menin–MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1–Menin and MLL3/4–UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials. Significance: Menin–MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin–MLL inhibitor–resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses. This article is highlighted in the In This Issue feature, p. 1

ChIP-Seq results

Sequences of sgRNAs and primers

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1–Menin and MLL3/4–UTX chromatin-modifying complexes that dictates response to Menin–MLL inhibitors. MLL1–Menin safeguards leukemia survival by impeding the binding of the MLL3/4–UTX complex at a subset of target gene promoters. Disrupting the Menin–MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1–Menin and MLL3/4–UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials.Significance:Menin–MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin–MLL inhibitor–resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses.This article is highlighted in the In This Issue feature, p. 1

RNA-Seq results

CRISPR screen results

Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.

Oxygen Minimum Zones (OMZs) are expanding in modern oceans due to anthropogenically-driven climate and environmental change. In the Eastern Mediterranean Sea (EMS), OMZs developed in the early Holocene as a result of decreased intermediate water ventilation, increasing temperature, and increased Nile discharge and primary productivity. Here, we report benthic foraminiferal numbers (BFN) and species abundances, together with redox-sensitive trace metals (RSTM), and iron and phosphorus speciation from two sediment cores sampled at intermediate depths (1200 and 1430 m) from the SE Levantine shelf. The main aim of our study is to better understand the sequence of redox changes during sapropel S1 deposition caused by biogeochemical processes affecting the sapropel intermediate water mass. The use of benthic foraminifera indices (diversity and oxygen) together with iron speciation and RSTM (V, Mo and U) enables detailed description of the changing oxygen/redox status of the overlying water. Prior to sapropel S1 deposition at ∼10.2 ka BP, RSTM suggest that the overlying water was well oxygenated, but benthic foraminifera numbers (BFN) suggest that oxygen levels had already begun to decrease. There was then a pulse of increased export carbon from the enlarged Nile flood plume, as shown by increased BFN at the beginning of sapropel S1. Shortly after, RSTM and Fe-S systematics suggest that the water column transitioned from dysoxic to anoxic, non-sulfidic. Anoxic conditions then persisted at 1200 m depth, but RSTM and benthic foraminifera indices suggest that deeper waters at 1430 m were more likely dysoxic, until the 8.2 ka BP global cooling event. The benthic foraminifera and inorganic redox proxies then suggest a second period of anoxic, non-sulfidic conditions, with a gradual return to well ventilated waters at the end of sapropel deposition at ∼6 ka BP. There was enhanced burial of authigenic P throughout sapropel deposition, derived from the deposition and subsequent release of organic-P and iron bound-P during diagenesis. Phosphorus recycling from the sediment and in the overlying water column added reactive P to these mid-depth waters, a process which has the potential to result in a positive feedback in systems where such waters are upwelled into the photic zone. The past EMS thus represents a template which can be used to predict biogeochemical changes in settings that evolve towards anoxic, non sulfidic conditions, which may occur in some areas as modern climate and environment change causes the continued expansion of modern OMZs and hypoxic areas adjacent to modern major rivers.

To improve the accuracy and generalization ability of hyperspectral image classification, a feature extraction method integrating principal component analysis (PCA) and local binary pattern (LBP) is developed for hyperspectral images in this article. The PCA is employed to reduce the dimension of the spectral features of hyperspectral images. The LBP with low computational complexity is used to extract the local spatial texture features of hyperspectral images to construct multifeature vectors. Then, the gray wolf optimization algorithm with global search capability is employed to optimize the parameters of kernel extreme learning machine (KELM) to construct an optimized KELM model, which is used to effectively realize a hyperspectral image classification (PLG-KELM) method. Finally, the Indian pines dataset, Houston dataset, and Pavia University dataset and an application of WHU-Hi-LongKou dataset are selected to verify the effectiveness of the PLG-KELM. The comparison experiment results show that the PLG-KELM can obtain higher classification accuracy, and takes on better generalization ability for small samples. It provides a new idea for processing hyperspectral images.

Background Physical rehabilitation is often prescribed immediately following a neurological event or a neurological diagnosis. However, many individuals require physical rehabilitation after hospital discharge. The purpose of this scoping review was to determine the amount of physical rehabilitation that individuals living in the community with neurological conditions receive to understand current global practices and assess gaps in research and service use. Methods This scoping review included observational studies that 1) involved adults living with a neurological condition, and 2) quantified the amount of rehabilitation being received in the community or outpatient hospital setting. Only literature published in English was considered. MEDLINE, EMBASE, AMED, CINAHL, Cochrane Library, and PEDro databases were searched from inception. Two independent reviewers screened titles and abstracts, followed by full texts, and data extraction. Mean annual hours of rehabilitation was estimated based on the amount of rehabilitation reported in the included studies. Results Overall, 18 studies were included after screen 14,698 articles. The estimated mean annual hours of rehabilitation varied greatly (4.9 to 155.1 h), with individuals with spinal cord injury and stroke receiving the greatest number of hours. Participants typically received more physical therapy than occupational therapy (difference range: 1 to 22 h/year). Lastly, only one study included individuals with progressive neurological conditions, highlighting a research gap. Discussion The amount of rehabilitation received by individuals with neurological conditions living in the community varies greatly. With such a wide range of time spent in rehabilitation, it is likely that the amount of rehabilitation being received by most individuals in the community is insufficient to improve function and quality of life. Future work should identify the barriers to accessing rehabilitation resources in the community and how much rehabilitation is needed to observe functional improvements.

The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded byMLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacological, and biochemical approaches in mouse and human systems, we discovered a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that MLL1-Menin safeguards leukemia survival by impeding binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of a tumor suppressor gene-program that is crucial for a therapeutic response in murine and human leukemia. We establish the therapeutic relevance of this mechanism by showing that CDK4/6 inhibitors allow re-activation of this tumor-suppressor program in Menin-inhibitor insensitive leukemia cells, mitigating treatment resistance. The discovery of a molecular switch between MLL1-Menin and MLL3/4-UTX complexes on chromatin sheds light on novel functions of these evolutionary conserved epigenetic mediators and is particularly relevant to understand and target molecular pathways determining response and resistance in ongoing phase 1/2 clinical trials.

The Mesoproterozoic era has long been considered a time of relative environmental and biological stasis. However, emerging insight suggests that this period may have been more dynamic than previously considered, both in terms of oxygenation and potential consequences for biological evolution. Nevertheless, our understanding of this immense period of time remains limited. To provide more detailed constraints on oxygenation dynamics, we report a multiproxy geochemical study of an early Mesoproterozoic (∼1600–1540 million years ago, Ma) carbonate-dominated succession from the North China craton. We include inorganic carbon isotope ( δ 13 C carb ), iron-speciation, and major and trace element data, in addition to molybdenum isotopic compositions ( δ 98 / 95 Mo ). These geochemical data support previous inferences of persistent anoxic and ferruginous deeper water conditions in the earliest Mesoproterozoic ocean, with limited oxygenation of surface waters. However, the behaviour of these redox-sensitive geochemical proxies reveals pulsed oxygenation events, with each event increasing the maximum depth of oxygenation, leading to overall progressive oxygenation of the ocean. During these pulsed oxygenation events we find the lightest Mo isotope signatures ever measured in the rock record, which we attribute to initial drawdown of isotopically light Mo in association with extensive Mn and Fe (oxyhydr)oxide precipitation, followed by diagenetic recycling. However, shallower water sediments deposited after the pulses of deeper water oxygenation more faithfully record the Mo isotopic composition of coeval seawater. For these samples, we utilise a single reservoir Mo cycling model, constrained by an updated estimate of Mesoproterozoic seawater Mo concentration, and scaled using a function associated with differential organic carbon flux between the shelf and basin. When scaled to modern rates of Mo accumulation under variable marine redox conditions, our modelling estimates suggest a minimum oxic seafloor area of ∼30% of the total seafloor area at ∼1540 Ma. It remains unclear whether the oxygenation observed across this ∼60 million year interval represents a progressive transition to a more persistently oxygenated ocean, or whether oceanic oxygen levels fluctuated considerably through the later Mesoproterozoic.