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.

Self-supervised Adversarial Training of Monocular Depth Estimation against Physical-World Attacks.

Monocular Depth Estimation (MDE) plays a vital role in applications such as autonomous driving. However, various attacks target MDE models, with physical attacks posing significant threats to system security. Traditional adversarial training methods, which require ground-truth labels, are not directly applicable to MDE models that lack ground-truth depth. Some self-supervised model hardening techniques (e.g., contrastive learning) overlook the domain knowledge of MDE, resulting in suboptimal performance. In this work, we introduce a novel self-supervised adversarial training approach for MDE models, leveraging view synthesis without the need for ground-truth depth. We enhance adversarial robustness against real-world attacks by incorporating L0-norm-bounded perturbation during training. We evaluate our method against supervised learning-based and contrastive learning-based approaches specifically designed for MDE. Our experiments with two representative MDE networks demonstrate improved robustness against various adversarial attacks, with minimal impact on benign performance. Our code: https://github.com/Bob-cheng/DepthModelHardening.

Multiome in the Same Cell Reveals the Impact of Osmotic Stress on Arabidopsis Root Tip Development at Single-Cell Level.

Cell-specific transcriptional regulatory networks (TRNs) play vital roles in plant development and response to environmental stresses. However, traditional single-cell mono-omics techniques are unable to directly capture the relationships and dynamics between different layers of molecular information within the same cells. While advanced algorithm facilitates merging scRNA-seq and scATAC-seq datasets, accurate data integration remains a challenge, particularly when investigating cell-type-specific TRNs. By examining gene expression and chromatin accessibility simultaneously in 16,670 Arabidopsis root tip nuclei, the TRNs are reconstructed that govern root tip development under osmotic stress. In contrast to commonly used computational integration at cell-type level, 12,968 peak-to-gene linkage is captured at the bona fide single-cell level and construct TRNs at an unprecedented resolution. Furthermore, the unprecedented datasets allow to more accurately reconstruct the coordinated changes of gene expression and chromatin states during cellular state transition. During root tip development, chromatin accessibility of initial cells precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for subsequent differentiation steps. Pseudo-time trajectory analysis reveal that osmotic stress can shift the functional differentiation of trichoblast. Candidate stress-related gene-linked cis-regulatory elements (gl-cCREs) as well as potential target genes are also identified, and uncovered large cellular heterogeneity under osmotic stress.

Structural basis for urate recognition and apigenin inhibition of human GLUT9.

Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, is the primary risk factor for the development of gout. The high-capacity urate transporter GLUT9 represents a promising target for gout treatment. Here, we present cryo-electron microscopy structures of human GLUT9 in complex with urate or its inhibitor apigenin at overall resolutions of 3.5 Å and 3.3 Å, respectively. In both structures, GLUT9 exhibits an inward open conformation, wherein the substrate binding pocket faces the intracellular side. These structures unveil the molecular basis for GLUT9's substrate preference of urate over glucose, and show that apigenin acts as a competitive inhibitor by occupying the substrate binding site. Our findings provide critical information for the development of specific inhibitors targeting GLUT9 as potential therapeutics for gout and hyperuricemia.

Efficient Control of Rhizoctonia solani Using Environmentally Friendly pH-Responsive Tannic Acid-Rosin Nano-Microcapsules.

A nanomicrocapsule system was constructed through the polymerization of tannic acid (TA) and emulsifier OP-10 (OP-10), followed by the chelation of iron ions, to develop a safe and effective method for controlling Rhizoctonia solani in agriculture. The encapsulated active component is a rosin-based triazole derivative (RTD) previously synthesized by our research group (RTD@OP10-TA-Fe). The encapsulation efficiency of the nanomicrocapsules is 82.39%, with an effective compound loading capacity of 96.49%. Through the encapsulation of the RTD via nanomicrocapsules, we improved its water solubility, optimized its stability, and increased its adhesion to the leaf surface. Under acidic conditions (pH = 5.0), the release rate of nanomicrocapsules at 96 h is 96.31 ± 0.8%, which is 2.04 times higher than the release rate under normal conditions (pH = 7.0). Additionally, the results of in vitro and in vivo antifungal assays indicate that compared with the original compound, the nanomicrocapsules exhibit superior antifungal activity (EC50 values of RTD and RTD@OP10-TA-Fe are 1.237 and 0.860 mg/L, respectively). The results of field efficacy trials indicate that compared with RTD, RTD@OP10-TA-Fe exhibits a more prolonged period of effectiveness. Even after 3 weeks, the antifungal rate of RTD@OP10-TA-Fe remains at 40%, whereas RTD, owing to degradation, shows an antifungal rate of 11.11% during the same period. Furthermore, safety assessment results indicate that compared with the control, RTD@OP10-TA-Fe has almost no impact on the growth of rice seedlings and exhibits low toxicity to zebrafish. This study provides valuable insights into controlling R. solani and enhancing the compound performance.

Glycine/alginate-based piezoelectric film consisting of a single, monolithic ß-glycine spherulite towards flexible and biodegradable force sensor.

Development of piezoelectric biomaterials with high piezoelectric performance, while possessing excellent flexibility, biocompatibility, and biodegradability still remains a great challenge. Herein, a flexible, biocompatible and biodegradable piezoelectric ß-glycine-alginate-glycerol (Gly-Alg-Glycerol) film with excellent in vitro and in vivo sensing performance was developed. Remarkably, a single, monolithic ß-glycine spherulite, instead of more commonly observed multiple spherulites, was formed in alginate matrix, thereby resulting in outstanding piezoelectric property, including high piezoelectric constant (7.2 pC/N) and high piezoelectric sensitivity (1.97 mV/kPa). The Gly-Alg-Glycerol film exhibited superior flexibility, enabling complex shape-shifting, e.g. origami pigeon, 40% tensile strain, and repeated bending and folding deformation without fracture. In vitro, the flexible Gly-Alg-Glycerol film sensor could detect subtle pulse signal, sound wave and recognize shear stress applied from different directions. In addition, we have demonstrated that the Gly-Alg-Glycerol film sensor sealed by polylactic acid and beeswax could serve as an in vivo sensor to monitor physiological pressure signals such as heartbeat, respiration and muscle movement. Finally, the Gly-Alg-Glycerol film possessed good biocompatibility, supporting the attachment and proliferation of rat mesenchymal stromal cells, and biodegradability, thereby showing great potential as biodegradable piezoelectric biomaterials for biomedical sensing applications.

miR-460b-5p promotes proliferation and differentiation of chicken myoblasts and targets RBM19 gene.

The meat production of broilers is crucial to economic benefits of broiler industries, while the slaughter performance of broilers is directly determined by skeletal muscle development. Hence, the broiler breeding for growth traits shows a great importance. As a kind of small noncoding RNA, microRNA (miRNA) can regulate the expression of multiple genes and perform a wide range of regulation in organisms. Currently, more and more studies have confirmed that miRNAs are closely associated with skeletal muscle development of chickens. Based on our previous miR-seq analysis (accession number: PRJNA668199), miR-460b-5p was screened as one of the key miRNAs probably involved in the growth regulation of chickens. However, the regulatory effect of miR-460b-5p on the development of chicken skeletal muscles is still unclear. Therefore, miR-460b-5p was further used for functional validation at the cellular level in this study. The expression pattern of miR-460b-5p was investigated in proliferation and differentiation stages of chicken primary myoblasts. It was showed that the expression level of miR-460b-5p gradually decreased from the proliferation stage (GM 50%) to the lowest at 24 h of differentiation. As differentiation proceeded, miR-460b-5p expression increased significantly, reaching the highest and stabilizing at 72 h and 96 h of differentiation. Through mRNA quantitative analysis of proliferation marker genes, CCK-8 and Edu assays, miR-460b-5p was found to significantly facilitate the transition of myoblasts from G1 to S phase and promote chicken myoblast proliferation. mRNA and protein quantitative analysis of differentiation marker genes, as well as the indirect immunofluorescence results of myotubes, revealed that miR-460b-5p significantly stimulated myotube development and promote chicken myoblast differentiation. In addition, the target relationship was validated for miR-460b-5p according to the dual-luciferase reporter assay and mRNA quantitative analysis, which indicates that miR-460b-5p was able to regulate RBM19 expression by specifically binding to the 3' UTR of RBM19. In summary, miR-460b-5p has positive regulatory effects on the proliferation and differentiation of chicken myoblasts, and RBM19 is a target gene of miR-460b-5p.

Exploration on the optimization of occupational injury and employment protection of takeout workers in the context of public health.

With the acceleration of the pace of urban life and the development of information technology, the takeout industry has emerged as the times require, which obtains intermediate costs by distributing goods to consumers. People pay more and more attention to public health, which requires takeout workers to drive as fast as possible to ensure the quality and safety of goods, but it also makes takeout workers suffer from various occupational injuries, such as car accidents, stomach diseases caused by eating disorders and long-term psychological pressure. This paper optimized the employment protection of takeout workers in combination with their professional characteristics. This paper used the analytic hierarchy process (AHP) to analyze the indicators that can evaluate the optimization effect of employment protection for takeout workers, and compared the occupation of takeout workers before and after employment protection. The experimental results showed that in Meituan takeout, the rationality of the average delivery management system before and after the optimization of employment protection was 47.2 and 64.4%, respectively; in ELEME takeout, the rationality of the average takeout distribution management system before and after the optimization of employment protection was 55.0% and 69.8%, respectively. Therefore, in the context of public health, the implementation of social security, employment relationship and optimization of service evaluation mechanism for outbound sales personnel can effectively improve the rationality of the delivery management system.

Genome-Wide Analysis of the KLF Gene Family in Chicken: Characterization and Expression Profile.

The kruppel-like factor (KLF) gene family is a group of transcription factors containing highly conserved zinc-finger motifs, which play a crucial role in cell proliferation and differentiation. Chicken has been widely used as a model animal for analyzing gene function, however, little is known about the function of the KLF gene family in chickens. In this study, we performed genome-wide studies of chicken KLF genes and analyzed their biological and expression characteristics. We identified 13 KLF genes from chickens. Our phylogenetic, motif, and conserved domain analyses indicate that the KLF gene family has remained conserved through evolution. Synteny analysis showed the collinear relationship among KLFs, which indicated that they had related biomolecular functions. Interaction network analysis revealed that KLFs worked with 20 genes in biological processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that KLF2 was involved in Apelin and Forkhead Box O (FOXO) signaling pathways. Moreover, qPCR showed that 13 KLF genes were expressed in the nine selected tissues and displayed various gene expression patterns in chickens. RNA-seq showed that KLF3 and KLF10 genes were differentially expressed in the normal and high-fat diet fed groups, and KLF4, KLF5, KLF6, KLF7, KLF9, KLF12, and KLF13 genes were differentially expressed between undifferentiated and differentiated chicken preadipocytes. Besides, RNA-seq also showed that KLF genes displayed different expression patterns in muscle at 11 and 16 embryonic days old, and in 1-day-old chickens. These results indicated that the KLF genes were involved in the development of muscle and fat in chickens. Our findings provide some valuable reference points for the subsequent study of the function of KLF genes.

Boosting adversarial robustness via self-paced adversarial training.

Adversarial training is considered one of the most effective methods to improve the adversarial robustness of deep neural networks. Despite the success, it still suffers from unsatisfactory performance and overfitting. Considering the intrinsic mechanism of adversarial training, recent studies adopt the idea of curriculum learning to alleviate overfitting. However, this also introduces new issues, that is, lacking the quantitative criterion for attacks' strength and catastrophic forgetting. To mitigate such issues, we propose the self-paced adversarial training (SPAT), which explicitly builds the learning process of adversarial training based on adversarial examples of the whole dataset. Specifically, our model is first trained with "easy" adversarial examples, and then is continuously enhanced by gradually adding "complex" adversarial examples. This way strengthens the ability to fit "complex" adversarial examples while holding in mind "easy" adversarial samples. To balance adversarial examples between classes, we determine the difficulty of the adversarial examples locally in each class. Notably, this learning paradigm can also be incorporated into other advanced methods for further boosting adversarial robustness. Experimental results show the effectiveness of our proposed model against various attacks on widely-used benchmarks. Especially, on CIFAR100, SPAT provides a boost of 1.7% (relatively 5.4%) in robust accuracy on the PGD10 attack and 3.9% (relatively 7.2%) in natural accuracy for AWP.

Exploration of Potential Target Genes of miR-24-3p in Chicken Myoblasts by Transcriptome Sequencing Analysis.

Broiler skeletal muscle growth is significantly influenced by miRNAs. Our earlier research demonstrated that miR-24-3p significantly suppressed the proliferation of chicken myoblasts while promoting their differentiation. The purpose of this study is to investigate miR-24-3p potential target genes in chickens. We collected myoblasts of Jinghai yellow chicken and transfected four samples with mimics of miR-24-3p and another four samples with mimic NC (negative control) for RNA-seq. We obtained 54.34 Gb of raw data in total and 50.79 Gb of clean data remained after filtering. Moreover, 11,635 genes were found to be co-expressed in these two groups. The mimic vs. NC comparison group contained 189 DEGs in total, 119 of which were significantly up-regulated and 70 of which were significantly down-regulated. Important biological process (BP) terminology such as nuclear chromosomal segregation, reproduction, and nuclear division were discovered by GO enrichment analysis for DEGs in the mimic vs. NC comparison group. KEGG pathway analysis showed that focal adhesion, cytokine-cytokine receptor interaction, the TGF-ß signaling pathway, and the MAPK signaling pathway were enriched in the top 20. Variation site analysis illustrated the SNP (single nucleotide polymorphisms) and INDEL (insertion-deletion) in the tested samples. By comparing the target genes predicted by miRDB (MicroRNA target prediction database) and TargetScan with the 189 DEGs found by the transcriptome sequencing, we discovered two up-regulated DEGs (NEURL1 and IQSEC3) and two down-regulated DEGs (REEP1 and ST6GAL1). Finally, we carried out qPCR experiments on eight DEGs and discovered that the qPCR results matched the sequencing outcomes. These findings will aid in identifying potential miR-24-3p target genes in chicken skeletal muscle and offer some new directions for upcoming research on broiler breeding.