Insufficient phosphorylation of STAT5 in Tregs inhibits the expression of BLIMP-1 but not IRF4, reduction the proportion of Tregs in pediatric aplastic anemia.

Deficiency in regulatory T cells (Tregs) is an important mechanism underlying the pathogenesis of pediatric aplastic anemia, but its specific mechanism is unclear. In our study, we aimed to investigate whether IL-2/STAT5 can regulate the proliferation of Tregs in aplastic anemia (AA) by regulating their expression of B lymphocyte-induced mature protein-1 (BLIMP-1) or interferon regulatory factor 4 (IRF4). Through clinical research and animal experiments, we found that poor activation of the IL-2/STAT5 signaling pathway may leads to low expression of BLIMP-1 in Tregs of children with AA, which leads to defects in the differentiation and proliferation of Tregs in AA. In AA model mice, treatment with IL-2c reversed the decrease in Treg proportions and reduction in Blimp-1 expression in Tregs by increasing the phosphorylation of Stat5 in Tregs. In AA, deficiency of IRF4 expression in Tregs is closely related to the deficiency of Tregs, but is not regulated by the IL-2/STAT5 pathway.

Enhancement of PRMT6 binding to a novel germline GATA1 mutation associated with congenital anemia.

Mutations in the master hematopoietic transcription factor GATA1 are often associated with functional defects in erythropoiesis and megakaryopoiesis. In this study, we identified a novel GATA1 germline mutation (c.1162delGG, p.Leu387Leufs*62) in a patient with congenital anemia and occasional thrombocytopenia. The C-terminal GATA1, a rarely studied mutational region, undergoes frameshifting translation as a consequence of this double-base deletion mutation. To investigate the specific function and pathogenic mechanism of this mutant, in vitro mutant models of stable re-expression cells were generated. The mutation was subsequently validated to cause diminished transcriptional activity of GATA1 and defective differentiation of erythroid and megakaryocytes. Using proximity labeling and mass spectrometry, we identified selective alterations in the proximal protein networks of the mutant, revealing decreased binding to a set of normal GATA1-interaction proteins, including the essential co-factor FOG1. Notably, our findings further demonstrated enhanced recruitment of the protein arginine methyltransferase PRMT6, which mediates histone modification at H3R2me2a and represses transcription activity. We also found an enhanced binding of this mutant GATA1/PRMT6 complex to the transcriptional regulatory elements of GATA1's target genes. Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function and the broader role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis.

Switchable Two-Dimensional AND and Exclusive OR Operation Based on Dual-Wavelength Metasurfaces.

Logic operation serves as the foundation and core element of computing networks; it will bring huge vitality to advanced information processing with its adaptation in the optical domain. As fundamental logic operations, AND and exclusive OR (XOR) operations serve a multitude of purposes, such as their ability to cooperate in enabling image processing and interpretation. Here, we propose and experimentally demonstrate a wavelength multiplexed AND and XOR function based on metasurfaces. By combining two cosine gratings with distinct frequencies and an initial phase difference of π/2, we extract the similarities and differences between two input images simultaneously by illuminating them with 445 and 633 nm wavelengths. Additionally, we explore its potential in information encryption, where overall security is enhanced by distributing distinct parts of initial information and encoded keys to different receivers. This design possesses the benefits of convenient mode switching and high-quality imaging, facilitating advanced applications in pattern recognition, machine vision, medical diagnosis, etc.

Mitochondria-targeted pentacyclic triterpene NIR-AIE derivatives for enhanced chemotherapeutic and chemo-photodynamic combined therapy.

Complexes formed by combining pentacyclic triterpenes (PTs) with Aggregation-Induced Emission luminogens (AIEgens), termed pentacyclic triterpene-aggregation induced emission (PT-AIEgen) complexes, merge the chemotherapeutic properties of PTs with the photocytotoxicity of AIEgens. In this study, we synthesized derivatives by connecting three types of triphenylamine (TPA) pyridinium derivatives with three common pentacyclic triterpenes. Altering the connecting group between the electron donor TPA and the electron acceptor pyridinium resulted in increased production of reactive oxygen species (ROS) by PT-AIEgens and a red-shift in their fluorescence emission spectra. Importantly, the fluorescence emission spectra of BA-3, OA-3, and UA-3 extended into the near-infrared (NIR) range, enabling NIR-AIE imaging of the sites where the derivatives aggregated. The incorporation of the pyridinium structure improved the mitochondrial targeting of PT-AIEgens, enhancing mitochondrial pathway-mediated cell apoptosis and improving the efficiency of chemotherapy (CT) and chemo-photodynamic combined therapy (CPCT) both in vivo and in vitro. Cellular fluorescence imaging demonstrated rapid cellular uptake and mitochondrial accumulation of BA-1 (-2, -3). Cell viability experiments revealed that BA-1 (-2), OA-1 (-2), and UA-1 (-2) exhibited superior CT cytotoxicity compared to their parent drugs, with BA-1 showing the most potent inhibitory effect on HeLa cells (IC50 = 1.19 µM). Furthermore, HeLa cells treated with BA-1 (1 µM), BA-2 (1.25 µM), and BA-3 (1 µM) exhibited survival rates of 2.99 % ± 0.05 % µM, 5.92 % ± 2.04 % µM, and 2.53 % ± 0.73 % µM, respectively, under white light irradiation. Mechanistic experiments revealed that derivatives induced cell apoptosis via the mitochondrial apoptosis pathway during both CT and CPCT. Remarkably, BA-1 and BA-3 in CPCT inhibited cancer cell proliferation in an in vivo melanoma mouse xenograft model. These results collectively encourage further research of PT-AIEgens as potential anticancer agents.

Perovskite single-pixel detector for dual-color metasurface imaging recognition in complex environment.

Highly efficient multi-dimensional data storage and extraction are two primary ends for the design and fabrication of emerging optical materials. Although metasurfaces show great potential in information storage due to their modulation for different degrees of freedom of light, a compact and efficient detector for relevant multi-dimensional data retrieval is still a challenge, especially in complex environments. Here, we demonstrate a multi-dimensional image storage and retrieval process by using a dual-color metasurface and a double-layer integrated perovskite single-pixel detector (DIP-SPD). Benefitting from the photoelectric response characteristics of the FAPbBr2.4I0.6 and FAPbI3 films and their stacked structure, our filter-free DIP-SPD can accurately reconstruct different colorful images stored in a metasurface within a single-round measurement, even in complex environments with scattering media or strong background noise. Our work not only provides a compact, filter-free, and noise-robust detector for colorful image extraction in a metasurface, but also paves the way for color imaging application of perovskite-like bandgap tunable materials.

In-plane emission manipulation of random optical modes by using a zero-index material.

In this work, we have proposed to implement a zero-index material (ZIM) to control the in-plane emission of planar random optical modes while maintaining the intrinsic disordered features. Light propagating through a medium with near-zero effective refractive index accumulates little phase change and is guided to the direction determined by the conservation law of momentum. By enclosing a disordered structure with a ZIM based on all-dielectric photonic crystal (PhC), broadband emission directionality improvement can be obtained. We find the maximum output directionality enhancement factor reaches 30, around 6-fold increase compared to that of the random mode without ZIM. The minimum divergence angle is ∼6° for single random optical mode and can be further reduced to ∼3.5° for incoherent multimode superposition in the far field. Despite the significant directionality enhancement, the random properties are well preserved, and the Q factors are even slightly improved. The method is robust and can be effectively applied to the disordered medium with different structural parameters, e.g., the filling fraction of scatterers, and different disordered structure designs with extended or strongly localized modes. The output direction of random optical modes can also be altered by further tailoring the boundary of ZIM. This work provides a novel and universal method to manipulate the in-plane emission direction as well as the directionality of disordered medium like random lasers, which might enable its on-chip integration with other functional devices.

The prognosis of breast cancer patients with bone metastasis could be potentially estimated based on blood routine test and biochemical examination at admission.

PURPOSE: Due to the poor and unpredictable prognosis of breast cancer (BC) patients with bone metastasis, it is necessary to find convenient and available prognostic predictors. This study aimed to recognize the clinical and prognostic factors related to clinical laboratory examination and to construct a prognostic nomogram for BC bone metastasis. METHODS: We retrospectively analyzed 32 candidate indicators from clinical features and laboratory examination data of 276 BC patients with bone metastasis. Univariate and multivariate regression analyses were performed to identify significant prognostic factors related to BC with bone metastasis. Nomogram was constructed and estimated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. RESULTS: Patients were randomly grouped into training (n = 197) and validation cohorts (n = 79). In training cohort, the multivariate regression analysis revealed that age, other organ metastasis sites, serum level of lactate dehydrogenase, globulin, white blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, and monocyte ratio were independent prognostic factors for BC with bone metastasis. The prognostic nomogram in training cohort exhibited areas under the ROC curve (AUCs) of 0.797, 0.782, and 0.794, respectively, for predicting 1-, 3-, and 5-year overall survival. In validation cohort, the nomogram still showed acceptable discrimination ability (AUCs: 0.723, 0.742, and 0.704) and calibration. CONCLUSION: This study constructed a novel prognostic nomogram for BC patients with bone metastasis. It could serve as a potential tool of survival assessment to help individual treatment decision-making for clinicians.

Our study investigated potential prognostic value of indicators from biochemical and blood routine examination for breast cancer patients with bone metastasis.Our study established a nomogram based on the indicators from biochemical and blood routine examination, which might enhance the ability to predict prognosis of breast cancer patients with bone metastasis.

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis.

Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were -4.26 ± 8.54 (3rd month), -4.72 ± 11.83 (6th month), -6.16 ± 15.41 (9th month), -6.07 ± 15.71 (12th month), and -7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

Phase-assisted Bessel-metasurface: a single-sized approach for simultaneous printing and holography.

Due to the unprecedented wavefront shaping capability, the metasurface has demonstrated state-of-the-art performances in various applications, especially in printing and holography. Recently, these two functions have been combined into a single metasurface chip to achieve a capability expansion. Despite the progress, current dual-mode metasurfaces are realized at the expense of an increase in the difficulty of the fabrication, reduction of the pixel resolution, or strict limitation in the illumination conditions. Inspired by the Jacobi-Anger expansion, a phase-assisted paradigm, called Bessel metasurface, has been proposed for simultaneous printing and holography. By elaborately arranging the orientations of the single-sized nanostructures with geometric phase modulation, the Bessel metasurface can not only encode a greyscale printing image in real space but can reconstruct a holographic image in k-space. With the merits of compactness, easy fabrication, convenient observation, and liberation of the illumination conditions, the design paradigm of the Bessel metasurface would have promising prospects in practical applications, including optical information storage, 3D stereoscopic displays, multifunctional optical devices, etc.

Immune desert in MMR-deficient tumors predicts poor responsiveness of immune checkpoint inhibition.

Background: Although many efforts have been devoted to identify biomarkers to predict the responsiveness of immune checkpoint inhibitors, including expression of programmed death-ligand 1 (PD-L1) and major histocompatibility complex (MHC) I, microsatellite instability (MSI), mismatch repair (MMR) defect, tumor mutation burden (TMB), tertiary lymphoid structures (TLSs), and several transcriptional signatures, the sensitivity of these indicators remains to be further improved. Materials and methods: Here, we integrated T-cell spatial distribution and intratumor transcriptional signals in predicting the response to immune checkpoint therapy in MMR-deficient tumors including tumors of Lynch syndrome (LS). Results: In both cohorts, MMR-deficient tumors displayed personalized tumor immune signatures, including inflamed, immune excluded, and immune desert, which were not only individual-specific but also organ-specific. Furthermore, the immune desert tumor exhibited a more malignant phenotype characterized by low differentiation adenocarcinoma, larger tumor sizes, and higher metastasis rate. Moreover, the tumor immune signatures associated with distinct populations of infiltrating immune cells were comparable to TLSs and more sensitive than transcriptional signature gene expression profiles (GEPs) in immunotherapy prediction. Surprisingly, the tumor immune signatures might arise from the somatic mutations. Notably, patients with MMR deficiency had benefited from the typing of immune signatures and later immune checkpoint inhibition. Conclusion: Our findings suggest that compared to PD-L1 expression, MMR, TMB, and GEPs, characterization of the tumor immune signatures in MMR-deficient tumors improves the efficiency of predicting the responsiveness of immune checkpoint inhibition.

All-Optical Multiplexed Meta-Differentiator for Tri-Mode Surface Morphology Observation.

Current optical differentiators are generally limited to realizing a single differential function once fabricated. Herein, a minimalist strategy in designing multiplexed differentiators (1st - and 2nd -order differentiations), implemented with a Malus metasurface consisting of single-sized nanostructures is proposed, thus improving the functionality of optical computing devices without the cost of complex design and nanofabrication. It is found that the proposed meta-differentiator exhibits excellent differential-computation performance and can be used for simultaneous outline detection and edge positioning of objects, corresponding to the functions of the 1st - and 2nd -order differentiations respectively. Experiments with biological specimens showcase that boundaries of biological tissues can not only be identified, but also the edge information for realizing high-precision edge positioning is highlighted. The study provides a paradigm in designing all-optical multiplexed computing meta-devices, and initiates tri-mode surface morphology observation by combining meta-differentiator with optical microscopes, which can find their applications in advanced biological imaging, large-scale defect detection, and high-speed pattern recognition, etc.

LILRB1+ immune cell infiltration identifies immunosuppressive microenvironment and dismal outcomes of patients with ovarian cancer.

OBJECTIVE: Immune checkpoint inhibitors are commonly used in various types of cancer, but their efficacy in ovarian cancer (OC) is limited. Thus, identifying novel immune-related therapeutic targets is crucial. Leukocyte immunoglobulin-like receptor subfamily B1 (LILRB1), a key receptor of human leukocyte antigen G (HLA-G), is involved in immune tolerance, but its role in tumor immunity remains unclear. METHODS: In this study, immunofluorescence was used to identify the location of LILRB1 in OC. The effect of LILRB1 expression on clinical outcomes in 217 patients with OC was analyzed retrospectively. A total of 585 patients with OC from the TCGA database were included to explore the relationship between LILRB1 and tumor microenvironment characteristics. RESULTS: LILRB1 was found to be expressed in tumor cells (TCs) and immune cells (ICs). High LILRB1+ ICs, but not LILRB1+ TCs, were associated with advanced FIGO stage, shorter survival outcomes, and worse adjuvant chemotherapy responses in OC patients. LILRB1 expression was also associated with high M2 macrophage infiltration, reduced activation of dendritic cells, and dysfunction of CD8+ T cells, suggesting an immunosuppressive phenotype. The combination of LILRB1+ ICs and CD8+ T cell levels could be used to distinguish patients with different clinical survival results. Moreover, LILRB1+ ICs infiltration with CD8+ T cells absence indicated inferior responsiveness to anti-PD-1/PD-L1 therapy. CONCLUSIONS: Tumor-infiltrating LILRB1+ ICs could be applied as an independent clinical prognosticator and a predictive biomarker for therapy responsiveness to OC. Further studies targeting the LILRB1 pathway should be conducted in the future.

Complete Tolerogenic Adjuvant Stimulates Regulatory T Cell Response to Immunization.

We have determined in mice the minimum composition required for forming a vaccine adjuvant that stimulates a regulatory T (Treg) cell response to immunization, and we named the adjuvant "complete tolerogenic adjuvant." This new kind of adjuvant may let us use the well-proven "Ag with adjuvant" form of immunization for inducing Treg cell-mediated Ag-specific immunosuppression. The minimum composition consists of dexamethasone, rapamycin, and monophosphoryl lipid A at a mass ratio of 8:20:3. By dissecting the respective role of each of these components during immunization, we have further shown why immunosuppressive and immunogenic agents are both needed for forming true adjuvants for Treg cells. This finding may guide the design of additional, and potentially more potent, complete tolerogenic adjuvants with which we may form numerous novel vaccines for treating immune diseases.

Toward Water-Immersion Programmable Meta-Display.

Heading toward next-generation intelligent display, dynamic control capability for meta-devices is critical for real world applications. Beyond the conventional electrical/optical/mechanical/thermal tuning methods, liquid immersion recently has emerged as a facile tuning mechanism which is easily accessible (especially water) and practically implementable for large tuning area. However, due to the longstanding and critical drawback of lacking independent-encoding capability, the state-of-art immersion approach remains incapable of pixel-level programmable switching. Here a water-immersion tuning scheme with pixel-scale programmability for dynamic meta-displays is proposed. Tunable meta-pixels can be engineered to construct spectral selective patterns at prior-/post- immersion states, such that a metasurface enables pixel-level transforming animations for dynamic multifield meta-displays, including near-field dual-nanoprints and far-field dual-holographic displays. The proposed water-immersion programmable approach for meta-display, benefitting from its large tuning area, facile operation and strong repeatability, may find a revolutionary path toward next-generation intelligent display with practical applications in dynamic display/encryption, information anticounterfeit/storage, and optical sensors.

Phase-assisted angular-multiplexing nanoprinting based on the Jacobi-Anger expansion.

Featuring with ultracompactness and subwavelength resolution, metasurface-assisted nanoprinting has been widely researched as an optical device for image display. It also provides a platform for information multiplexing, and a series of multiplexed works based on incident polarizations, operating wavelengths and observation angles have emerged. However, the angular-multiplexing nanoprinting is realized at the cost of image resolution reduction or the increase of fabrication difficulty, hindering its practical applications. Here, inspired by the Jacobi-Anger expansion, a phase-assisted design paradigm, called Bessel metasurface, was proposed for angular multiplexing nanoprinting. By elaborately designing the phase distribution of the Bessel metasurface, the target images can be encoded into the desired observation angles, reaching angular multiplexing. With the merits of ultracompactness and easy fabrication, we believe that our design strategy would be attractive in the real-world applications, including optical information storage, encryption/concealment, multifunctional switchable optical devices, and 3D stereoscopic displays, etc.

Dual-channel anticounterfeiting color-nanoprinting with a single-size nanostructured metasurface.

Metasurface-based structural-colors are usually implemented by changing the dimensions of nanostructures to produce different spectral responses. Therefore, a single-size nanostructured metasurface usually cannot display structural-colors since it has only one design degree of freedom (DOF), i.e., the orientation angles of nanostructures. Here, we show structural-color nanoprinting images can be generated with a single-size nanostructured metasurface, enabled by designing the anisotropic nanostructure with different spectral responses along its long- and short-axis directions, respectively. More interestingly, the concept of orientation degeneracy of nanostructures can be applied in the metasurface design, which shows two spectral modulations can be implemented under different polarization directions of output light, thus extending the color-nanoprinting from single-channel to dual-channel. The proposed dual-channel metasurface used for anticounterfeiting color-nanoprinting has presented the advantages of ultra-compactness, high information capacity, and vivid colors, which can develop broad applications in fields such as high-end anticounterfeiting, high-density information storage, optical encryption, etc.

Tri-channel metasurface for watermarked structural-color nanoprinting and holographic imaging.

Structural-color nanoprinting, which can generate vivid colors with spatial resolution at subwavelength level, possesses potential market in optical anticounterfeiting and information encryption. Herein, we propose an ultracompact metasurface with a single-cell design strategy to establish three independent information channels for simultaneous watermarked structural-color nanoprinting and holographic imaging. Dual-channel spectrum manipulation and single-channel phase manipulation are combined together by elaborately introducing the orientation degeneracy into the design of variable dielectric nanobricks. Hence, a structural-color nanoprinting image covered with polarization-dependent watermarks and a holographic image can be respectively generated under different decoded environments. The proposed metasurface shows a flexible method for tri-channel image display with high information capacity, and exhibits dual-mode anticounterfeiting with double safeguards, i.e., polarization-controlled watermarks and a far-field holographic image. This study provides a feasible route to develop multifunctional metasurfaces for applications including optical anticounterfeiting, information encryption and security, information multiplexing, etc.

Artificial Hyper Compound Eyes Enable Variable-Focus Imaging on both Curved and Flat Surfaces.

The artificial compound eye (ACE) with zoom imaging requires complex power sources. Meanwhile, its curved substrate makes it difficult for the ACE to realize the zoom imaging on flat surfaces. To realize a wide field of view and a zoom function on both curved and flat surfaces simultaneously, a novel ACE is proposed, which is a bionic design inspired by an ancient creature, trilobite. Compared with a dragonfly, photosensitive units of a trilobite's compound eye are composed of ommatidia with different focal lengths. By learning from this concept, an artificial hyper compound eye (AHCE) was fabricated. Its basic components are five microlenses with different curvatures, and they are capable of being treated as five ommatidia with different focal lengths. Five ommatidia form a photosensitive unit to realize a zoom function. AHCE is capable of variable-focus imaging on curved surfaces. With the information share function, we found that the AHCE not only images on curved surfaces but also has a zoom-imaging function on flat surfaces. The results confirm that the AHCE demonstrates an advanced imaging capability, a variable-focus imaging function on both curved and flat surfaces, which may open new opportunities in developing advanced micro-optical devices.

SRF-derived miR210 and miR30c both repress beating cardiomyocyte formation in the differentiation system of embryoid body.

Serum response factor (SRF) cooperates with various co-factors to manage the specification of diverse cell lineages during heart development. Many microRNAs mediate the function of SRF in this process. However, how are miR210 and miR30c involved in the decision of cardiac cell fates remains to be explored. In this study, we found that SRF directly controlled the cardiac expression of miR210. Both miR210 and miR30c blocked the formation of beating cardiomyocyte during embryoid body (EB) differentiation, a cellular model widely used for studying cardiogenesis. Both of anticipated microRNA targets and differentially expressed genes in day8 EBs were systematically determined and enriched with gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) and Reactome. Functional enrichments of prediction microRNA targets and down-regulated genes in day8 EBs of miR210 suggested the importance of PI3K-Akt signal and ETS2 in miR210 inhibition of cardiomyocyte differentiation. Similar analyses revealed that miR30c repressed both developmental progress and the adrenergic signaling in cardiomyocytes during the differentiation of EBs. Taken together, SRF directs the expression of miR210 and miR30c, and they repress cardiac development via inhibiting the differentiation of cardiac muscle cell lineage as well as the cell proliferation. Through the regulation of specific microRNAs, the complication of SRF's function in heart development is emphasized.

Identification of mutant p53-specific proteins interaction network using TurboID-based proximity labeling.

BACKGROUNDS: Although several studies on mutant p53 reported cancer-promoting activities via "gain-of-function", the mechanism underlying these differences in function between p53 R175H, R175P, and p53 wild-type (WT) remains unclear. METHODS: Linking miniTurbo with p53 WT, R175H, and R175P, the expression of fusion and biotinylated proteins were assessed by Western blotting. The function and subcellular localization of fusion proteins were detected by apoptosis assay and immunofluorescence, respectively. Biotinylated proteins were analyzed by liquid chromatography-tandem mass spectrometry, followed by bioinformatics analysis. Small-scale pull-downs and Co-Immunoprecipitation were performed to validate the interaction between mutant or p53 WT and biotinylated proteins. RESULTS: The fusion protein's cellular localization and function were consistent with those of previous studies on the corresponding p53. Comparative profiles of R175H versus WT showed that most of the interacting proteins belonged to the intracellular organelle lumen, and the pathways involved were metabolism and genetic information processing. Comparative profiles of R175P versus WT suggested that the majority of the interacting proteins belonged to the intracellular organelle lumen and the extracellular membrane-bounded organelle, and the pathways involved were metabolism and genetic information processing pathways. The comparison between R175H and R175P revealed that most interacting proteins belonged to the organelle lumen, and pathways involved were genetic information processing pathways. Finally, the mutation of p53 significantly altered the interaction with the target proteins were confirmed. CONCLUSION: We verified the reliability of the miniTurbo system and obtained candidate targets of mutant p53, which provided new thoughts on the mechanism of mutant p53 gain-of-function and new potential targets for cancer therapy.