YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

A novel Cu(II)-assisted peptide fluorescent probe for highly sensitive detection of glyphosate in real samples: real application in test strips and smartphone.

Glyphosate (Glyp) is an organophosphorus herbicide, and its abuse causes potential harm to the environment and human health. Thus, the development of simple and portable methods for rapid and visual detection of glyphosate is of great importance. Herein, we successfully developed a new fluorescent probe L with dansyl fluorophore as a fluorescent dye and tetrapeptide (Ala-Ser-Arg-His-NH2) as a recognition group. According to the design, L exhibited a specific fluorescence quenching response to Cu2+ and formed an L-Cu2+ ensemble with a molecular ratio of 2:1, demonstrating a limit of detection (LOD) as low as 12.04 nM. Interestingly, the L-Cu2+ ensemble as a relay response probe exhibited a specific fluorescence "off-on" response to glyphosate without interference from other pesticides and anions based on the strong complexation of glyphosate and Cu2+. The LOD of the L-Cu2+ ensemble for glyphosate was calculated as 12.59 nM. Additionally, the results of three recovery experiments with real samples showed that L has good practicability and accuracy in detecting glyphosate. Test strips were also fabricated to achieve facile detection of glyphosate to demonstrate the practical application potential of the L-Cu2+ ensemble. The L-Cu2+ ensemble was integrated with a smartphone for semi-quantification of glyphosate in a field environment under a 365 nm UV lamp.

Antiviral activity evaluation and action mechanism of myricetin derivatives containing thioether quinoline moiety.

A variety of myricetin derivatives containing thioether quinoline moiety were designed and synthesized. Their structures of title compounds were determined by 1H NMR, 13C NMR, 19F NMR, and HRMS. Single-crystal X-ray diffraction experiments were carried out with B4. Antiviral activity indicated that some of the target compounds exhibited remarkable anti-tobacco mosaic virus (TMV) activity. In particular, compound B6 possessed significant activity. The half maximal effective concentration (EC50) value of the curative activity of compound B6 was 169.0 µg/mL, which was superior to the control agent ningnanmycin (227.2 µg/mL). Meanwhile, the EC50 value of the protective activity of compound B6 was 86.5 µg/mL, which was better than ningnanmycin (179.2 µg/mL). Microscale thermophoresis (MST) indicated that compound B6 had a strong binding capability to the tobacco mosaic virus coat protein (TMV-CP) with a dissociation constant (Kd) value of 0.013 µmol/L, which was superior to that of myricitrin (61.447 µmol/L) and ningnanmycin (3.215 µmol/L). And the molecular docking studies were consistent with the experimental results. Therefore, these novel myricetin derivatives containing thioether quinoline moiety could become potential alternative templates for novel antiviral agents.

Video Captioning Using Global-Local Representation.

Video captioning is a challenging task as it needs to accurately transform visual understanding into natural language description. To date, state-of-the-art methods inadequately model global-local vision representation for sentence generation, leaving plenty of room for improvement. In this work, we approach the video captioning task from a new perspective and propose a GLR framework, namely a global-local representation granularity. Our GLR demonstrates three advantages over the prior efforts. First, we propose a simple solution, which exploits extensive vision representations from different video ranges to improve linguistic expression. Second, we devise a novel global-local encoder, which encodes different video representations including long-range, short-range and local-keyframe, to produce rich semantic vocabulary for obtaining a descriptive granularity of video contents across frames. Finally, we introduce the progressive training strategy which can effectively organize feature learning to incur optimal captioning behavior. Evaluated on the MSR-VTT and MSVD dataset, we outperform recent state-of-the-art methods including a well-tuned SA-LSTM baseline by a significant margin, with shorter training schedules. Because of its simplicity and efficacy, we hope that our GLR could serve as a strong baseline for many video understanding tasks besides video captioning. Code will be available.

Antiviral Activities of Novel Myricetin Derivatives Containing 1,3,4-Oxadiazole Bisthioether.

A class of novel myricetin derivatives containing 1,3,4-oxadiazole bisthioether were synthesized. The results of antiviral biological activity demonstrated that the partially compounds exhibited good antiviral effects against tobacco mosaic virus. The in vivo curative and protective activities of compound E12 against TMV was quite significant. The EC50 value of the curative activity of E12 was 128.8 µg/mL, while the value of ningnanmycin was 296.4 µg/mL. Similarly, the EC50 value of the protective activity of E12 was 99.1 µg/mL, while the value of ningnanmycin was 307.6 µg/mL. The microscale thermophoresis data indicated that the binding value of ningnanmycin and TMV-CP was 2.726±1.301 µM, which was not as good as the binding value of E12 and TMV-CP was 0.029±0.013 µM. This study showed that novel myricetin derivatives containing 1,3,4-oxadiazole bisthioether may be a kind of agricultural antiviral drugs with great potential.

Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state.

Lysyl oxidases (LOXs), a type of copper- and lysyl tyrosylquinone (LTQ) -dependent amine oxidase, catalyze the oxidative deamination of lysine residues of extracellular matrix (ECM) proteins such as elastins and collagens and generate aldehyde groups. The oxidative deamination of lysine represents the foundational step for the cross-linking of elastin and collagen and thus is crucial for ECM modeling. Despite their physiological significance, the structure of this important family of enzymes remains elusive. Here we report the crystal structure of human lysyl oxidase-like 2 (hLOXL2) at 2.4-Å resolution. Unexpectedly, the copper-binding site of hLOXL2 is occupied by zinc, which blocks LTQ generation and the enzymatic activity of hLOXL2 in our in vitro assay. Biochemical analysis confirms that copper loading robustly activates hLOXL2 and supports LTQ formation. Furthermore, the LTQ precursor residues in the structure are distanced by 16.6 Å, corroborating the notion that the present structure may represent a precursor state and that pronounced conformational rearrangements would be required for protein activation. The structure presented here establishes an important foundation for understanding the structure-function relationship of LOX proteins and will facilitate LOX-targeting drug discovery.

Cellular and Molecular State of Myeloid Leukemia Stem Cells.

Leukemia stem cells (LSCs) are leukemia-initiating population with the capacity to self-renew, differentiate, and stay quiescent. Human hematopoietic malignancies such as chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are derived from this cell population. LSCs are also responsible for disease relapse due to its resistance to drug treatment. This rare cell population is phenotypically and functionally heterogeneous. Increasing evidence indicates that this heterogeneous cellular state of LSCs might determine the different drug sensitivity and is the major reason for disease relapse. In here, focusing on myeloid leukemia stem cells, we describe the biological features including cellular and molecular state, heterogeneity of LSCs, and the dynamic cross talk between LSCs and bone marrow microenvironment. These specific features of LSCs highlight the dynamic cellular state of LSCs, and further exploring on it might provide potential therapeutic targets that are important for eliminating LSCs.

C-H Functionalization of Amines via Alkene-Derived Nucleophiles through Cooperative Action of Chiral and Achiral Lewis Acid Catalysts: Applications in Enantioselective Synthesis.

Catalytic transformations of α-amino C-H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out under oxidative conditions and require precious metal-based catalysts. Here, we disclose a strategy for an enantioselective union of N-alkylamines and α,ß-unsaturated compounds, performed under redox-neutral conditions, and promoted through concerted action of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg-PyBOX complex. Thus, a wide variety of ß-amino carbonyl compounds may be synthesized, with complete atom economy, through stereoselective reaction of an in situ-generated enantiomerically enriched Mg-enolate and an appropriate electrophile.

Enantioselective Direct Mannich-Type Reactions Catalyzed by Frustrated Lewis Acid/Brønsted Base Complexes.

An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond-activated aldimines delivers ß-aminocarbonyl compounds with high enantiomeric purity.

Enzyme-Mediated Modification of Single-Domain Antibodies for Imaging Modalities with Different Characteristics.

Antibodies are currently the fastest-growing class of therapeutics. Although naked antibodies have proven valuable as pharmaceutical agents, they have some limitations, such as low tissue penetration and a long circulatory half-life. They have been conjugated to toxic payloads, PEGs, or radioisotopes to increase and optimize their therapeutic efficacy. Although nonspecific conjugation is suitable for most in vitro applications, it has become evident that site specifically modified antibodies may have advantages for in vivo applications. Herein we describe a novel approach in which the antibody fragment is tagged with two handles: one for the introduction of a fluorophore or (18)F isotope, and the second for further modification of the fragment with a PEG moiety or a second antibody fragment to tune its circulatory half-life or its avidity. Such constructs, which recognize Class II MHC products and CD11b, showed high avidity and specificity. They were used to image cancers and could detect small tumors.