MIF as a potential diagnostic and prognostic biomarker for triple-negative breast cancer that correlates with the polarization of M2 macrophages.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a crucial role in antitumor immunity. However, the role of MIF in influencing the tumor microenvironment (TME) and prognosis of triple-negative breast cancer (TNBC) remains to be elucidated. Using R, we analyzed single-cell RNA sequencing (scRNA-seq) data of 41 567 cells from 10 TNBC tumor samples and spatial transcriptomic data from two patients. Relationships between MIF expression and immune cell infiltration, clinicopathological stage, and survival prognosis were determined using samples from The Cancer Genome Atlas (TCGA) and validated in a clinical cohort using immunohistochemistry. Analysis of scRNA-seq data revealed that MIF secreted by epithelial cells in TNBC patients could regulate the polarization of macrophages into the M2 phenotype, which plays a key role in modulating the TME. Spatial transcriptomic data also showed that epithelial cells (tumor cells) and MIF were proximally located. Analysis of TCGA samples confirmed that tumor tissues of patients with high MIF expression were enriched with M2 macrophages and showed a higher T stage. High MIF expression was significantly associated with poor patient prognosis. Immunohistochemical staining showed high MIF expression was associated with younger patients and worse clinicopathological staging. MIF secreted by epithelial cells may represent a potential biomarker for the diagnosis and prognosis of TNBC and may promote TNBC invasion by remodeling the tumor immune microenvironment.

Erratum to: Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter.

The original version of this article (Weng et al., 2023) unfortunately contained a mistake. In Acknowledgments, the number (No. 226-2022-00213) of the Fundamental Research Funds for the Central Universities is wrong. The correct number should be No. 2022FZZX01-33.

Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter. / é€šè¿‡åˆ†å­åŠ¨åŠ›å­¦æ¨¡æ‹Ÿæ–¹æ³•ç ”ç©¶c-Myb在mim-1启动子区域伪回文序列的结合特性揭示DNA特异性识别机制.

This study aims to gain insight into the DNA-specific recognition mechanism of c-Myb transcription factor during the regulation of cell early differentiation and proliferation. Therefore, we chose the chicken myeloid gene, mitochondrial import protein 1 (mim-1), as a target to study the binding specificity between potential dual-Myb-binding sites. The c-Myb-binding site in mim-1 is a pseudo-palindromic sequence AACGGTT, which contains two AACNG consensuses. Simulation studies in different biological scenarios revealed that c-Myb binding with mim-1 in the forward strand (complex F) ismore stable than that inthereverse strand (complex R). The principal component analysis (PCA) dynamics trajectory analyses suggested an opening motion of the recognition helices of R2 and R3 (R2R3), resulting in the dissociation of DNA from c-Myb in complex R at 330 K, triggered by the reduced electrostatic potential on the surface of R2R3. Furthermore, the DNA confirmation and hydrogen-bond interaction analyses indicated that the major groove width of DNA increased in complex R, which affected on the hydrogen-bond formation ability between R2R3 and DNA, and directly resulted in the dissociation of DNA from R2R3. The steered molecular dynamics (SMD) simulation studies also suggested that the electrostatic potential, major groove width, and hydrogen bonds made major contribution to the DNA|-specific recognition. In vitro trials confirmed the simulation results that c-Myb specifically bound to mim-1 in the forward strand. This study indicates that the three-dimensional (3D) structure features play an important role in the DNA-specific recognition mechanism by c-Myb besides the AACNG consensuses, which is beneficial to understanding the cell early differentiation and proliferation regulated by c-Myb, as well as the prediction of novel c-Myb-binding motifs in tumorigenesis.

A Comprehensive Study of 3-D Vision-Based Robot Manipulation.

Robot manipulation, for example, pick-and-place manipulation, is broadly used for intelligent manufacturing with industrial robots, ocean engineering with underwater robots, service robots, or even healthcare with medical robots. Most traditional robot manipulations adopt 2-D vision systems with plane hypotheses and can only generate 3-DOF (degrees of freedom) pose accordingly. To mimic human intelligence and endow the robot with more flexible working capabilities, 3-D vision-based robot manipulation has been studied. However, this task is still challenging in the open world especially for general object recognition and pose estimation with occlusion in cluttered backgrounds and human-like flexible manipulation. In this article, we propose a comprehensive analysis of recent progress about the 3-D vision for robot manipulation, including 3-D data acquisition and representation, robot-vision calibration, 3-D object detection/recognition, 6-DOF pose estimation, grasping estimation, and motion planning. We then present some public datasets, evaluation criteria, comparisons, and challenges. Finally, the related application domains of robot manipulation are given, and some future directions and open problems are studied as well.

Two distinct males absent on the first (MOF)-containing histone acetyltransferases are involved in the epithelial-mesenchymal transition in different ways in human cells.

Human males absent on the first (MOF), a histone acetyltransferase (HAT), forms male-specific lethal (MSL) and non-specific lethal (NSL), two multiprotein HATs, in cells. MSL was originally discovered in dosage compensation study in Drosophila that can specifically acetylate H4K16, while NSL can simultaneously catalyze the H4 at K5, K8, and K16 sites. However, comparative studies of the two HATs in regulating specific biological functions are rarely reported. Here, we present evidence to argue that MSL and NSL function in different ways in the epithelial-to-mesenchymal transition (EMT) process. At first, CRISPR/Cas9-mediated MSL1 (a key subunit of the MSL)-knockout (KO) and NSL3 (a key subunit of the NSL)-KO cells seem to prefer to grow in clusters. Interestingly, the former promotes cell survival and clonal formation, while the latter has the opposite effect on it. Cell staining revealed that MSL1-KO leads to multipolarized spindles, while NSL3-KO causes more lumen-like cells. Furthermore, in Transwell experiments, silencing of MSL1 promotes cell invasion in 293 T, MCF-7, and MDA-MB-231 cells. In contrast, the inhibitory effects on cell invasion are observed in the same NSL3-silenced cells. Consistent with this, mesenchymal biomarkers, like N-cadherin, vimentin, and snail, are negatively correlated with the expression level of MSL1; however, a positive relationship between these proteins and NSL3 in cells has been found. Further studies have clarified that MSL1, but not NSL3, can specifically bind to the E-box-containing Snail promoter region and thereby negatively regulate Snail transactivation. Also, silencing of MSL1 promotes the lung metastasis of B16F10 melanoma cells in mice. Finally, ChIP-Seq analysis indicated that the NSL may be mainly involved in phosphoinositide-mediated signaling pathways. Taken together, the MOF-containing MSL and NSL HATs may regulate the EMT process in different ways in order to respond to different stimuli.

The Non-Specific Lethal (NSL) Histone Acetyltransferase Complex Transcriptionally Regulates Yin Yang 1-Mediated Cell Proliferation in Human Cells.

The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase (HAT) complex acetylates histone H4 at lysine K5, K8, and K16. This complex shares several subunits with other epigenetic regulatory enzymes, which highlights the complexity of its intracellular function. However, the effect of the NSL HAT complex on the genome and target genes in human cells is still unclear. By using a CRISPR/Cas9-mediated NSL3-knockout 293T cell line and chromatin immunoprecipitation-sequencing (ChIP-Seq) approaches, we identified more than 100 genes as NSL HAT transcriptional targets, including several transcription factors, such as Yin Yang 1 (YY1) which are mainly involved in cell proliferation, biological adhesion, and metabolic processes. We found here that the ChIP-Seq peaks of MOF and NSL3 co-localized with H4K16ac, H3K4me2, and H3K4me3 at the transcriptional start site of YY1. In addition, both the mRNA and protein expression levels of YY1 were regulated by silencing or overexpressing NSL HAT. Interestingly, the expression levels of cell division cycle 6, a downstream target gene of YY1, were regulated by MOF or NSL3. In addition, the suppressed clonogenic ability of HepG2 cells caused by siNSL3 was reversed by overexpressing YY1, suggesting the involvement of YY1 in NSL HAT functioning. Additionally, de novo motif analysis of MOF and NSL3 targets indicated that the NSL HAT complex may recognize the specific DNA-binding sites in the promoter region of target genes in order to regulate their transcription.

L3DOC: Lifelong 3D Object Classification.

3D object classification has been widely applied in both academic and industrial scenarios. However, most state-of-the-art algorithms rely on a fixed object classification task set, which cannot tackle the scenario when a new 3D object classification task is coming. Meanwhile, the existing lifelong learning models can easily destroy the learned tasks performance, due to the unordered, large-scale, and irregular 3D geometry data. To address these challenges, we propose a Lifelong 3D Object Classification (i.e., L3DOC) model, which can consecutively learn new 3D object classification tasks via imitating "human learning". More specifically, the core idea of our model is to capture and store the cross-task common knowledge of 3D geometry data in a 3D neural network, named as point-knowledge, through employing layer-wise point-knowledge factorization architecture. Afterwards, a task-relevant knowledge distillation mechanism is employed to connect the current task to previous relevant tasks and effectively prevent catastrophic forgetting. It consists of a point-knowledge distillation module and a transforming-space distillation module, which transfers the accumulated point-knowledge from previous tasks and soft-transfers the compact factorized representations of the transforming-space, respectively. To our best knowledge, the proposed L3DOC algorithm is the first attempt to perform deep learning on 3D object classification tasks in a lifelong learning way. Extensive experiments on several point cloud benchmarks illustrate the superiority of our L3DOC model over the state-of-the-art lifelong learning methods.

Polyphotosensitizer nanogels for GSH-responsive histone deacetylase inhibitors delivery and enhanced cancer photodynamic therapy.

Photodynamic therapy (PDT) is one of the non-invasive and selective treatment methodologies for cancer. However, many highly efficient photosensitizers (PSs) are usually low physiological solubility, limited bioavailability and tending aggregation, impeding the effectiveness of PDT, as well as cancer resistance of PDT further reduce its therapeutic effect. Though some smart delivery systems have been developed, the problem of photosensitizer leakage/release has not been completely solved. Herein, we developed a smart therapeutic nanoplatform based on polyphotosensitizer nanogel as novel nanophotosensitizers and drug carriers. Moreover, by loading of histone deacetylase inhibitors (SAHA), it allows for enhanced synergistic therapy strategy of prostate cancer via inhibiting HIF-1α and VEGF pathways of cancer cells involved in PDT resistance. Our study presents the well-designed nanoplatform of nanogel-Ce6, which could serve as a photodynamic agent without Ce6 molecules release in the responsive environment, offering the potential to encapsulate diverse functional components for smart drug release and imaging-guided combination therapy in vitro and in vivo.

O-GlcNAc-Modification of NSL3 at Thr755 Site Maintains the Holoenzyme Activity of MOF/NSL Histone Acetyltransfease Complex.

Both OGT1 (O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase isoform 1) and NSL3 (nonspecific lethal protein 3) are crucial components of the MOF (males absent on the first)/NSL histone acetyltransferase complex. We previously described how global histone H4 acetylation levels were modulated by OGT1/O-GlcNAcylation-mediated NSL3 stability. However, the specific modification site of NSL3 and its molecular mechanism of protein stability remain unknown. Here, we present evidence from biochemical experiments arguing that O-GlcNAcylation of NSL3 at Thr755 is tightly associated with holoenzyme activity of the MOF/NSL complex. Using in vitro O-GlcNAc-transferase assays combined with mass spectrometry, we suppose that the residue Thr755 on NSL3 C-terminus is the major site O-GlcNAc-modified by OGT1. Importantly, O-GlcNAcylation of this site is involved in the regulation of the ubiquitin-degradation of NSL3, because this site mutation (T755A) promotes the ubiquitin-mediated degradation of NSL3. Further in-depth research found that ubiquitin conjugating enzyme E2 S (UBE2S) accelerated the degradation of NSL3 via direct binding to it. Interestingly, OGT1 and UBE2S competitively bind to NSL3, suggesting the coordination of OGT1-UBE2S in regulating NSL3 stability. Furthermore, O-GlcNAcylation of NSL3 Thr755 site regulates the histone H4 acetylation levels at lysine 5, 8, and 16, suggesting that the O-GlcNAcylation of NSL3 at Thr755 is required for maintaining the integrity and holoenzyme activity of the MOF/NSL complex. In colony formation assays, we found that the integrity of the complex impacts the proliferation of the lung carcinoma type II epithelium-like A549 cells. Taken together, our results provide new insight into the elucidation of the molecular mechanism of the MOF/NSL complex.