RUNX1::ETO and CBFß::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core-binding factor-acute myeloid leukaemia.

Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFß::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFß::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.

Overemphasized role of preceding strong El Niño in generating multi-year La Niña events.

Previous studies have emphasized the significance of a strong El Niño preceding La Niña (LN) in the formation of multi-year LN events due to the slow recharge-discharge ocean heat content process. However, observational analyses from 1900 to 2022 reveal that the majority (64%) of multi-year LN events did not necessitate a preceding strong El Niño to generate their second LN, suggesting an overemphasis on traditional views. Instead, here we show that a negative phase of the North Pacific Meridional Mode (PMM) during spring, when the first LN begins to decay, activates the mechanism responsible for triggering another LN and producing a multi-year event. The westward extension of the first LN's cold anomalies, which interact directly with the eastern edge of the western Pacific warm pool, is highlighted as a crucial factor in the occurrence of a negative PMM. Additionally, the PMM mechanism can create a third LN, leading to triple-dip events.

Seasonally-reversed trends in the subtropical Northwestern Pacific linked to asymmetric AMO influences.

This study identifies seasonally-reversed trends in Kuroshio strength and sea surface temperatures (SSTs) within the western North Pacific (WNP) since the 1990s, specifically in the 22° N-28° N region. These trends are characterized by increases during summer and decreases during winter. The seasonally-reversed trends are a result of the asymmetric responses of the WNP to a shift towards the positive phase of the Atlantic multidecadal oscillation (AMO) around the same period. The positive AMO induces an anomalous descent over the North Pacific during summer, leading to the direct strengthening of the gyre. However, during winter, it triggers an anomalous descent over the tropical Pacific, which excites a poleward wavetrain impacting the WNP and causing gyre weakening. The associated responses of the East Asian monsoon and China Coastal Current contribute to the observed seasonally-reversed SST trends. It is noteworthy that the seasonally-reversed trends in gyre strength and SSTs are predominantly observed north of 20° N in the WNP. This limitation arises because the anomalous cyclone within the winter poleward wavetrain is located north of this latitude boundary. Specifically, the clearest trends in gyre strength are observed in the northern segment of the Kuroshio, while the manifestation of SST trends in the Taiwan Strait could potentially be attributed to the influence and enhancement of the East Asian monsoon and the China Coastal Current. Due to the limited length of observational data, statistical significance of some of the signals discussed is rather limited. A CESM1 pacemaker experiments is further conducted to confirm the asymmetric responses of the North Pacific to the AMO between the summer and winter seasons.

[Application of Desulphurized Gypsum with Straw to Improve Physicochemical Properties of Saline-alkali Land in Yellow River Delta].

In order to explore the effect of combining straw and desulphurized gypsum on improving coastal saline-alkali soil, taking the alkaline saline soil in the Yellow River Delta as the research object, six treatments including the control (CK), desulphurized gypsum (DG), medium straw amount (MS), desulphurized gypsum+low straw amount (DGLS), desulphurized gypsum+medium straw amount (DGMS), and desulphurized gypsum+high straw amount (DGHS) were set up through a field location experiment. Combined with the aggregate classification method, the changes in bulk density, total porosity, pH, soluble salt content, microbial biomass carbon, dissolved organic carbon, new carbon, and aggregate organic carbon of coastal saline alkali soil under different treatments were compared. The results showed that the MS and DGHS treatments significantly reduced soil bulk density and increased soil total porosity, water content, and average weight diameter. The pH and exchange sodium percentage decreased significantly under all treatments, and there was no significant difference. DG treatment significantly reduced the soil sodium adsorption ratio. Compared with that in the MS treatment, the soil sodium adsorption ratio of DGLS, DGMS, and DGHS showed a further decreasing trend, with a decrease range of 57%-66%. Compared with MS, soil soluble Na+ decreased by 27.92%, 32.23%, and 20.15% under the DGLS, DGMS, and DGHS treatments, whereas the soil soluble Ca2+ and SO42- contents increased significantly. Compared with that in CK, all treatments could significantly reduce Cl- content, and there was no significant difference among all treatments. Compared with that in MS, microbial biomass carbon and dissolved organic carbon were significantly increased by 113% and 147% by DGMS and 22.81% and 28.24% by DGHS, respectively. The new carbon formation of DGLS, DGMS, and DGHS was 67%, 114%, and 175% higher than that of MS, respectively. The average size proportion of fine aggregates treated by DGLS, DGMS, and DGHS was 29.12% higher than that treated by MS. Straw returning and application of desulfurized gypsum increased the organic carbon content of coarse aggregates and fine aggregates in salinized soil. The average value of new carbon formation in coarse aggregates and fine aggregates treated by DGMS and DGHS was 233% and 142% higher than that treated by MS, respectively. Desulphurized gypsum applied to soil did not lead to soil heavy metal pollution, and the soil heavy metal content of different treatments was lower than the secondary standard of the soil environmental quality standard. These results can provide scientific basis for the improvement and utilization of coastal saline-alkali soil and the comprehensive utilization of industrial and agricultural wastes in the Yellow River Delta.

Low-modal-crosstalk orthogonal combine reception for degenerate modes in IM/DD MDM transmission.

Weakly-coupled mode division multiplexing (MDM) techniques supporting intensity modulation and direct detection (IM/DD) transmission is a promising candidate to enhance the capacity of short-reach applications such as optical interconnections, in which low-modal-crosstalk mode multiplexers/demultiplexers (MMUX/MDEMUX) are highly desired. In this paper, we firstly propose an all-fiber low-modal-crosstalk orthogonal combine reception scheme for degenerate linearly-polarized (LP) modes, in which signals in both degenerate modes are firstly demultiplexed into the LP01 mode of single-mode fibers, and then are multiplexed into mutually orthogonal LP01 and LP11 modes of a two-mode fiber for simultaneous detection. Then a pair of 4-LP-mode MMUX/MDEMUX consisting of cascaded mode-selective couplers and orthogonal combiners are fabricated with side-polishing processing, which achieve low back-to-back modal crosstalk of lower than -18.51 dB and insertion loss of lower than 3.81 dB for all the 4 modes. Finally, a stable real-time 4 modes × 4λ × 10 Gb/s MDM-wavelength division multiplexing (WDM) transmission over 20-km few-mode fiber is experimentally demonstrated. The proposed scheme is scalable to support more modes and can pave the way to practical implementation of IM/DD MDM transmission applications.

Glutathione disrupts galectin-10 Charcot-Leyden crystal formation to possibly ameliorate eosinophil-based diseases such as asthma.

Charcot-Leyden crystals (CLCs) are the hallmark of many eosinophilic-based diseases, such as asthma. Here, we report that reduced glutathione (GSH) disrupts CLCs and inhibits crystallization of human galectin-10 (Gal-10). GSH has no effect on CLCs from monkeys ( Macaca fascicularis or M. mulatta), even though monkey Gal-10s contain Cys29 and Cys32. Interestingly, human Gal-10 contains another cysteine residue (Cys57). Because GSH cannot disrupt CLCs formed by the human Gal-10 variant C57A or inhibit its crystallization, the effects of GSH on human Gal-10 or CLCs most likely occur by chemical modification of Cys57. We further report the crystal structures of Gal-10 from M. fascicularis and M. mulatta, along with their ability to bind to lactose and inhibit erythrocyte agglutination. Structural comparison with human Gal-10 shows that Cys57 and Gln75 within the ligand binding site are responsible for the loss of lactose binding. Pull-down experiments and mass spectrometry show that human Gal-10 interacts with tubulin α-1B, with GSH, GTP and Mg 2+ stabilizing this interaction and colchicine inhibiting it. Overall, this study enhances our understanding of Gal-10 function and CLC formation and suggests that GSH may be used as a pharmaceutical agent to ameliorate CLC-induced diseases.

North Atlantic oscillation controls multidecadal changes in the North Tropical Atlantic-Pacific connection.

By exciting subtropical teleconnections, sea surface temperature (SST) anomalies in the North Tropical Atlantic (NTA) during boreal spring can trigger El Niño-Southern Oscillation (ENSO) events in the following boreal winter, thereby providing a precursor for ENSO predictability. However, this NTA-ENSO connection is not stationary, and it varies considerably over multidecadal timescales, which cannot be directly explained by the Atlantic multidecadal oscillation or the global warming trend. Here we show that multidecadal changes in the NTA-ENSO connection are principally controlled by multidecadal variability associated with the North Atlantic Oscillation (NAO). During the positive phase of the NAO, the amplification of the NTA impact on ENSO mainly arises from strengthening of the boreal spring mean precipitation over the equatorial Atlantic and enhancement of the persistence of NTA SST anomalies, which enhance the NTA influence by exciting stronger and more persistent subtropical teleconnections. Our findings show that multidecadal variability of the NAO is key to understanding the impacts of the NTA SST on the tropical Pacific Ocean.

The transcript NR 134251.1 of lncRNA APTR with an opposite function to all transcripts inhibits proliferation and induces apoptosis by regulating proliferation and apoptosis-related genes.

Arsenic (As) exposure has been a global public health concern for hundreds of millions worldwide. LncRNA APTR (Alu-mediated p21 transcriptional regulator) plays an essential role in tumor growth and development. However, its function in arsenic-induced toxicological responses is still unknown. In this study, we found that the expressions of all transcripts and the transcript NR 134251.1 of APTR were increased in a dose-dependent manner in 16HBE cells treated with sodium arsenite (NaAsO2). Silencing the transcript NR 134251.1 of APTR inhibited cell proliferation and induced apoptosis. However, silencing all transcripts of APTR had the opposite function to the transcript NR 134251.1. Then we examined the protein level of the proliferation and apoptosis-related genes after silencing the transcript NR 134251.1 of APTR. The results showed that silencing the transcript NR 134251.1 of APTR up-regulated the expression of transcription factor E2F1 and regulated its downstream genes involved in proliferation and apoptosis, including p53, phospho-p53-S392, phospho-p53-T55, p21, Cyclin D1, PUMA, Fas, Bim, BIK, Caspase-3, Caspase-7, and Cyt-c. In conclusion, arsenic induced APTR expression and the transcript NR 134251.1 of APTR have an opposite function to all transcripts, providing a theoretical basis for the prevention and treatment of arsenic exposure.

Tracking westerly wind directions over Europe since the middle Holocene.

The variability of the northern westerlies has been considered as one of the key elements for modern and past climate evolution. Their multiscale behavior and underlying control mechanisms, however, are incompletely understood, owing to the complex dynamics of Atlantic sea-level pressures. Here, we present a multi-annually resolved record of the westerly drift over the past 6,500 years from northern Italy. In combination with more than 20 other westerly-sensitive records, our results depict the non-stationary westerly-affected regions over mainland Europe on multi-decadal to multi-centennial time scales, showing that the direction of the westerlies has changed with respect to the migrations of the North Atlantic centers of action since the middle Holocene. Our findings suggest the crucial role of the migrations of the North Atlantic dipole in modulating the westerly-affected domain over Europe, possibly modulated by Atlantic Ocean variability.

Neoantigen-specific TCR-T cell-based immunotherapy for acute myeloid leukemia.

Neoantigens derived from non-synonymous somatic mutations are restricted to malignant cells and are thus considered ideal targets for T cell receptor (TCR)-based immunotherapy. Adoptive transfer of T cells bearing neoantigen-specific TCRs exhibits the ability to preferentially target tumor cells while remaining harmless to normal cells. High-avidity TCRs specific for neoantigens expressed on AML cells have been identified in vitro and verified using xenograft mouse models. Preclinical studies of these neoantigen-specific TCR-T cells are underway and offer great promise as safe and effective therapies. Additionally, TCR-based immunotherapies targeting tumor-associated antigens are used in early-phase clinical trials for the treatment of AML and show encouraging anti-leukemic effects. These clinical experiences support the application of TCR-T cells that are specifically designed to recognize neoantigens. In this review, we will provide a detailed profile of verified neoantigens in AML, describe the strategies to identify neoantigen-specific TCRs, and discuss the potential of neoantigen-specific T-cell-based immunotherapy in AML.

Effect of Straw and Wood Ash on Soil Carbon Sequestration and Bacterial Community in a Calcareous Soil.

Soil fertility can be improved by effectively utilizing agricultural waste. Straw can supply energy and wood ash adds nutrients to improve soil quality. However, few kinds of research have investigated the effect of wood ash and straw on soil carbon sequestration and the soil bacterial population, particularly in calcareous soils. The main goal of this current study was to quantify the impact of a combination of wood ash and straw on the indicators described above using stable δ13C isotope analyses by applying wheat straw to calcareous soil under a long-term C4 crop rotation. The incubation experiment included four treatments as follows: (i) no amendment (Control); (ii) amendment with wood ash (W); (iii) amendment with straw (S); and (iv) a combined amendment of straw and wood ash (SW). Our results showed that sequestration of soil inorganic carbon (SIC) in the SW and W treatments was higher (an average of 7.78%) than that in the S and Control treatments. The sequestered soil organic carbon (SOC) in the SW treatment was 1.25-fold greater than that in the S treatment, while there was no evident effect on the SOC content compared with straw alone. The microbial biomass carbon increased under SW by 143.33%, S by 102.23%, and W by 13.89% relative to control. The dissolved organic carbon increased under SW by 112.0%, S by 66.61%, and W by 37.33% relative to the control. The pH and electrical conductivity were higher in the SW and W treatments than in the S treatment and the control. The SW was conducive to maintaining soil enzymatic activities and bacterial diversity. Bacteroidetes and Actinobacteriota were dominant in SW, while the Acidobacteria phyla were dominant in the S treatment. The diversity of bacteria in the soil and community composition of the bacteria were predominantly assessed by the levels of water-soluble K, pH, and electrical conductivity. The incorporation of straw and wood ash is probably more effective at improving SIC and SOC sequestration and ameliorates the soil microhabitat.

Multi-year El Niño events tied to the North Pacific Oscillation.

Multi-year El Niño events induce severe and persistent floods and droughts worldwide, with significant socioeconomic impacts, but the causes of their long-lasting behaviors are still not fully understood. Here we present a two-way feedback mechanism between the tropics and extratropics to argue that extratropical atmospheric variability associated with the North Pacific Oscillation (NPO) is a key source of multi-year El Niño events. The NPO during boreal winter can trigger a Central Pacific El Niño during the subsequent winter, which excites atmospheric teleconnections to the extratropics that re-energize the NPO variability, then re-triggers another El Niño event in the following winter, finally resulting in persistent El Niño-like states. Model experiments, with the NPO forcing assimilated to constrain atmospheric circulation, reproduce the observed connection between NPO forcing and the occurrence of multi-year El Niño events. Future projections of Coupled Model Intercomparison Project phases 5 and 6 models demonstrate that with enhanced NPO variability under future anthropogenic forcing, more frequent multi-year El Niño events should be expected. We conclude that properly accounting for the effects of the NPO on the evolution of El Niño events may improve multi-year El Niño prediction and projection.

The increased frequency of combined El Niño and positive IOD events since 1965s and its impacts on maritime continent hydroclimates.

The Indian and Pacific Oceans surround the Maritime Continent (MC). Major modes of sea surface temperature variability in both oceans, including the Indian Ocean Dipole (IOD) and El Niño-Southern Oscillation (ENSO), can strongly affect precipitation on the MC. The prevalence of fires in the MC is closely associated with precipitation amount and terrestrial water storage in September and October. Precipitation and terrestrial water storage, which is a measurement of hydrological drought conditions, are significantly modulated by Indian Ocean Dipole (IOD) and El Niño events. We utilize long-term datasets to study the combined effects of ENSO and the IOD on MC precipitation during the past 100 years (1900-2019) and find that the reductions in MC precipitation and terrestrial water storage are more pronounced during years when El Niño and a positive phase of the IOD (pIOD) coincided. The combined negative effects are produced mainly through an enhanced reduction of upward motion over the MC. Coincident El Niño-pIOD events have occurred more frequently after 1965. However, climate models do not project a higher occurrence of coincident El Niño-pIOD events in a severely warming condition, implying that not the global warming but the natural variability might be the leading cause of this phenomenon.

Structural basis for glucosylsucrose synthesis by a member of the α-1,2-glucosyltransferase family.

Glucosylsucroses are potentially useful as additives in cosmetic and pharmaceutical formulations. Although enzymatic synthesis of glucosylsucroses is the most efficient method for their production, the key enzyme that produces them has remained unknown. Here, we report that glucosylsucrose synthase from (TeGSS) catalyzes the synthesis of glucosylsucrose using sucrose and UDP-glucose as substrates. These saccharides are homologous to glucosylsucroses produced by sp. PCC 7120 (referred to as protein alr1000). When the ratio of UDP-glucose to sucrose is relatively high, TeGSS from cyanobacteria can hydrolyze excess UDP-glucose to UDP and glucose, indicating that sucrose provides a feedback mechanism for the control of glucosylsucrose synthesis. In the present study, we solved the crystal structure of TeGSS bound to UDP and sucrose. Our structure shows that the catalytic site contains a circular region that may allow glucosylsucroses with a right-hand helical structure to enter the catalytic site. Because active site residues Tyr18 and Arg179 are proximal to UDP and sucrose, we mutate these residues (., Y18F and R179A) and show that they exhibit very low activity, supporting their role as catalytic groups. Overall, our study provides insight into the catalytic mechanism of TeGSS.

Actin binding to galectin-13/placental protein-13 occurs independently of the galectin canonical ligand-binding site.

The gene for galectin-13 (Gal-13, placental protein 13) is only present in primates, and its low expression level in maternal serum may promote preeclampsia. In the present study, we used pull-down experiments and biolayer interferometry to assess the interaction between Gal-13 and actin. These studies uncovered that human Gal-13 (hGal-13) and Saimiri boliviensis boliviensis (sGal-13) strongly bind to α- and ß-/γ-actin, with Ca2+ and adenosine triphosphate, significantly enhancing the interactions. This in turn suggests that h/sGal-13 may inhibit myosin-induced contraction when vascular smooth muscle cells undergo polarization. Here, we solved the crystal structure of sGal-13 bound to lactose and found that it exists as a monomer in contrast to hGal-13 which is a dimer. The distribution of sGal-13 in HeLa cells is similar to that of hGal-13, indicating that monomeric Gal-13 is the primary form in cells. Even though sGal-13 binds to actin, hGal-13 ligand-binding site mutants do not influence hGal-13/actin binding, whereas the monomeric mutant C136S/C138S binds to actin more strongly than the wild-type hGal-13. Overall, our study demonstrates that monomeric Gal-13 binds to actin, an interaction that is independent of the galectin canonical ligand-binding site.

Detection of tyrosinase in living cells using an Enteromorpha Prolifera based fluorescent probe.

Melanoma, the skin cancer with the highest mortality rate, can be diagnosed at the early stage by detecting unique biomarkers. Over-expressed tyrosinase has been confirmed by dozens of clinical studies as an independent factor to evaluate the malignancy of melanoma. Using Enteromorpha Prolifera as the raw material, herein we develop a novel fluorescent probe, ECDY, which can sensitively detect the tyrosinase activity in different types of cells. More importantly, melanoma cells can be specifically distinguished through cell lysate measurements as well as the whole-cell imaging technique. Mechanically, the tyrosine groups on the surface of ECDY can be specifically recognized by tyrosinase and further converted into dopaquinone, which consequently causes the intramolecular fluorescence quenching of the probe through photoinduced electron transfer (PET). Tyrosinase can be detected within 20 min in the solution, and the detection limit is as low as 0.067 U mL-1. For the in vitro demonstration, we evaluate the fluorescence decay of ECDY in response to the intracellular tyrosinase activity within the lysate of various cell lines, including non-cancerous, non-melanoma cancerous, and mouse melanoma ones. The experimental results verify that ECDY can accurately measure the apparent tyrosinase activity in different cell lines and detect melanoma cell lysate specifically. The confocal fluorescence imaging experiments further demonstrate that ECDY can distinguish melanoma cells from others significantly. We believe that ECDY provides a new strategy for the efficient detection of tyrosinase and melanoma cells, and is expected to apply as a clinical diagnosis platform.

Zonally contrasting shifts of the tropical rainbelt in response to climate change.

Future changes in the position of the intertropical convergence zone (ITCZ; a narrow band of heavy precipitation in the tropics) with climate change could affect the livelihood and food security of billions of people. Although models predict a future narrowing of the ITCZ, uncertainties remain large regarding its future position, with most past work focusing on zonal-mean shifts. Here we use projections from 27 state-of-the-art (CMIP6) climate models and document a robust zonally-varying ITCZ response to the SSP3-7.0 scenario by 2100, with a northward shift over eastern Africa and the Indian Ocean, and a southward shift in the eastern Pacific and Atlantic Oceans. The zonally-varying response is consistent with changes in the divergent atmospheric energy transport, and sector-mean shifts of the energy flux equator. Our analysis provides insight about mechanisms influencing the future position of the tropical rainbelt, and may allow for more robust projections of climate change impacts.

Anti-Diabetic Indole-Terpenoids From Penicillium sp. HFF16 Isolated From the Rhizosphere Soil of Cynanchum bungei Decne.

Finding novel anti-diabetic compounds with effective suppression activities against hepatic glucagon response is urgently required for the development of new drugs against diabetes. Fungi are well known for their ability to produce new bioactive secondary metabolites. As part of our ongoing research, five new indole-terpenoids (1-5), named encindolenes D-H, were isolated from the fungus Penicillium sp. HFF16 from the rhizosphere soil of Cynanchum bungei Decne. The structures of the compounds were elucidated by spectroscopic data and ECD analysis. In the anti-diabetic activity assay, compounds 1-5 could inhibit the hepatic glucose production with EC50 values of 17.6, 30.1, 21.3, 9.6, and 9.9 µM, respectively, and decrease the cAMP contents in glucagon-induced HepG2 cells.

An Atlantic-driven rapid circulation change in the North Pacific Ocean during the late 1990s.

Interbasin interactions have been increasingly emphasized in recent years due to their roles in shaping climate trends and the global warming hiatus in the northern hemisphere. The profound influence from the North Atlantic on the Tropical Pacific has been a primary focus. In this study, we conducted observational analyses and numerical modeling experiments to show that the North Atlantic has also strongly influenced the Extratropical North Pacific. A rapid and synchronous change in the atmospheric and oceanic circulations was observed in the North Pacific during the late 1990s. The change was driven by the transbasin influence from the Atlantic Ocean. During the positive phase of the Atlantic Multidecadal Oscillation (AMO) since the 1990s, the anomalously warm North Atlantic triggers a series of zonally symmetric and asymmetric transbasin teleconnections involving the Inter-tropical Convergence Zone (ITCZ), Walker and Hadley circulations, and Rossby wave propagation that lead to a decrease in wind stress curls over the Pacific subtropics, resulting in an abrupt weakening in the North Pacific subtropical gyre (NPSG) and the Kuroshio Current.