Salvianolic acid B alleviates autoimmunity in Treg-deficient mice via inhibiting IL2-STAT5 signaling.

Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.

Crosstalk mitigation of a controllable annular auto-focusing vortex beam array in a turbulent atmosphere.

In this paper, we introduce a new type of controllable auto-focusing vortex beam array named annular quasi-Airy vortex beam array (QAVBA), which can reduce the crosstalk among different orbital angular momentum (OAM) modes of optical vortex. The effects of initial beam parameters of annular QAVBA and propagation conditions on the OAM mode propagation performance are investigated. The results indicate that the topological angle θ, the topological charge m, and the decay parameter α could manipulate the auto-focusing characteristics of annular QAVBA and regulate the crosstalk of OAM modes. The crosstalk among OAM modes increases with the turbulence strength. Interestingly, the annular QAVBA with obtuse topological angle is favorable for the OAM mode transmitting at far propagation distance or in strong atmospheric turbulence when the decay parameter α is large enough for the energy of annular QAVBA mainly concentrating on the main light ring. Our research provides a reference for optimizing the design of light sources and free-space optical communication system with annular QAVBA.

Propagation dynamics of the controllable circular Airyprime beam in the Kerr medium.

In this paper, we study the propagation dynamics of the circular Airyprime beam (CAPB) in the Kerr medium for the first time. We investigate the effects of the astigmatism factor, the chirp factor, and vortices on the CAPB propagating in the Kerr medium. At the same time, we are also introducing a special-shaped Airyprime beam (SAPB) during its propagation. The transmission characteristics of the CAPB and the SAPB in the Kerr medium are compared under identical conditions. Our theoretical results provide additional possibilities for CAPB modulation in the Kerr medium, thereby promising wider applicability of CAPB in various research areas.

Inhibition of UBA6 by inosine augments tumour immunogenicity and responses.

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and hence generating an immunologically hotter microenvironment. We find that inosine directly inhibits UBA6 in tumour cells, and lower level of UBA6 makes the tumour more immunogenic and this is reflected in favourable outcome following ICB therapy in human melanomas. Transplanted mouse melanoma and breast cancer cells with genetic ablation of Uba6 show higher sensitivity to ICB than wild type tumours. Thus, we provide evidence of an inosine-regulated UBA6-dependent pathway governing tumour-intrinsic immunogenicity and hence sensitivity to immune checkpoint inhibition, which might provide targets to overcome ICB resistance.

EEF1A2 interacts with HSP90AB1 to promote lung adenocarcinoma metastasis via enhancing TGF-ß/SMAD signalling.

BACKGROUND: Eukaryotic protein translation elongation factor 1α2 (EEF1A2) is an oncogene that promotes the progression of breast and pancreatic cancer. In this study, we aimed to elucidate the oncogenic function of EEF1A2 in the metastasis of lung adenocarcinoma (LUAD). METHODS: Immunohistochemistry and western blot were used to study EEF1A2 expression levels in LUAD tissues and cells, respectively. The role of EEF1A2 in LUAD progression were investigated in vitro and in vivo. We identified potential EEF1A2-binding proteins by liquid chromatography-electrospray mass spectrometry (LC-MS)/MS. Protein-protein interactions were determined by immunofluorescence and co-immunoprecipitation (Co-IP). RESULTS: In this study, we report that EEF1A2 mediates the epithelial-mesenchymal transformation (EMT), to promote the metastasis of LUAD cells in vitro and in vivo. Moreover, EEF1A2 interacts with HSP90AB1 to increase TGFß Receptor (TßR)-I, and TßRII expression, followed by enhanced SMAD3 and pSMAD3 expression and nuclear localisation, which promotes the EMT of LUAD cells. Overexpression of EEF1A2 in cancer tissues is associated with poor prognosis and short survival of patients with LUAD. CONCLUSIONS: These findings underscore the molecular functions of EEF1A2 in LUAD metastasis and indicate that EEF1A2 represents a promising target in the treatment of aggressive LUAD.

High-resolution quantitative phase imaging based on a spatial light modulator and incremental binary random sampling.

We propose a single-beam high-resolution quantitative phase imaging method based on a spatial light modulator (SLM) and an incremental binary random sampling (IBRS) algorithm. In this method, the image of the test object presents on the image sensor through an optical microscopy system composed of an objective lens and a collimating lens. A transmittance SLM displaying a group of well-designed IBRS patterns is inserted in the optical microscopy system to modulate the object wavefront. The phase information of the object image can be quantitatively retrieved from the recorded intensities using the IBRS algorithm and the amplitude obtained directly from the diffraction intensity. The IBRS algorithm employed in our method has higher accuracy for phase retrieval compared with our previously proposed complementary random sampling algorithm, which is confirmed by simulations. Further, we demonstrate experimentally the feasibility of our method through several examples: phase imaging of immersion oil droplets with a diffraction-limited lateral resolution of 1.54 µm and a few microbiological specimens with 0.70 µm. Experimental results reveal that our proposed method provides a feasible single-beam technique for quantitative phase imaging with a high spatial resolution.

Conventional solitons and bound-state solitons in an erbium-doped fiber laser mode-locked by TiSe2-based saturable absorber.

Conventional solitons (CSs) as well as bound-state solitons in a passively mode-locked erbium-doped fiber (EDF) laser based on 1 T-phase titanium diselenide (1 T-TiSe2) saturable absorber (SA) have been systematically demonstrated for the first time. The mode locker is assembled by sandwiching the 1 T-TiSe2 film between two fiber ferrules to improve compatibility with the all-fiber-integrated ring cavity configuration. The modulation depth, saturation intensity and nonsaturable loss of the prepared 1 T-TiSe2 SA are 14.36%, 1.33 MW cm-2 and 9.44%, respectively. The system is switchable between two states: CS and bound-state CS, by carefully adjusting the orientations of the polarization controller (PC). In the CS mode-locked regime, the oscillating wavelength is centered at 1558.294 nm with a pulse duration of 1.74 ps, a pulse repetition rate of 3.23 MHz and a maximum average output power of 2.904 mW. In the bound-state CS regime, two identical solitons form the bound-state pulses with a temporal separation of 6.1 ps, and the bound-state pulses are equally distributed at a repetition rate of 3.23 MHz, corresponding to the fundamental cavity repetition rate. The experimental results further indicate that 1 T-TiSe2 SA is competitive with the existing SAs explored so far and will promote the applications of 1 T-TiSe2-based SAs in the field of ultrafast lasers.

Modulation of release mechanisms of methylene blue (MB) monomers and dimers from silica-MB@shellac synthesized by antisolvent crystallization.

Release behaviors of drugs from drug deliveries are crucial for the enhancement of therapy efficiency, reduction of toxicity and patient compliance. Herein, antisolvent crystallization is employed to coat methlyene blue (MB)-loaded silica by shellac precipitation (silica-MB@shellac), which is simultaneously induced by outward diffusion of H+ ions from particular silica-MB. The encapsulation of shellac shell on silica-MB modulates the aggregation state of MB, which endows silica-MB@shellac a decreased MB's thermal stability, enhanced photoluminescence intensity, improved stability against in vitro reduction by ascorbic acid and retained photodynamic therapy activity. From the absorbance of MB supernatant obtained during incubation, the concentrations of MB monomers and dimers are determined via a non-linear regression analysis to investigate the influence of shellac coating on MB's release mechanisms from silica-MB@shellac. According to the simulated models, small diffusion constants of MB are caused by limited diffusion through shellac shells with high compaction degrees. These are observed for samples synthesized under high supersaturation degree during antisolvent crystallization. High degree of supersaturation is achieved through increasing shellac concentration, additive amount and dropping rate of antisolvent, as well as decreasing pH values of aqueous buffers as antisolvent. Furthermore, a combined mechanism of Fickian diffusion and Case-IΙ relaxation is proposed to describe the release behaviors of MB monomer and dimers from silica-MB@shellac. Therefore, this work may shed light on the encapsulation method of polymer on drug-loaded powders and the control of aggregation states of photosensitizers to promote the photoluminescence intensity, photodynamic therapy efficiency and controlled release behaviors.

Fully controlled photonic spin in highly confined optical field.

As an intrinsic attribute of light, the spin angular momentum (SAM) of photons has aroused considerable attention because of the fascinating properties emerging from light-matter interactions. We show that a diffraction-limited focal field with a steerable photonic spin structure in three dimensions can be produced under a 4π microscopic system. This is achieved by focusing two counter-propagating configurable vector beams produced in the coherent superposition of three different beams with x-polarization, y-polarization, and radial-polarization. By altering the amplitude factors of these resultant beams, the ratios between the three mutually orthogonal polarized components can be freely tuned within the focal plane, thereby allowing dynamic control over the spin orientation and ellipticity of the tightly focused optical field. The results demonstrated in this paper may find applications in spin-controlled nanophotonics.

Passively Q-switched erbium-doped fiber laser based on antimonene as saturable absorber.

A passively ${Q}$-switched erbium-doped fiber (EDF) laser based on antimonene saturable absorber is exclusively and systematically demonstrated. Few-layer antimonene nanosheets are prepared and a passively ${Q}$-switched EDF laser based on the saturable absorption feature of antimonene is implemented. The pulse repetition rate varies from 25.3 to 76.7 kHz when the pump power changes from 41 to 345 mW. The shortest pulse duration is 1.58 µs with pulse energy of 37.9 nJ. The experiment displays some new characteristics, which indicates that there is still much work to do before the mechanism of saturable absorption characteristics of antimonene is completely revealed.

Proteomic Analysis of the Molecular Mechanism of Lovastatin Inhibiting the Growth of Nasopharyngeal Carcinoma Cells.

Metabolic abnormalities are one of the essential features of tumors. Increasingly more studies have shown that lovastatin, a lipid-reducing drug, has visible inhibitory effects on tumors, but it has not been reported in nasopharyngeal carcinoma. In this paper, we explored the effects of lovastatin on the growth of nasopharyngeal carcinoma cells and its possible molecular mechanisms. After treating nasopharyngeal carcinoma cells with different concentrations of lovastatin, we found that lovastatin can inhibit the growth of nasopharyngeal carcinoma in a time- and dose-dependent manner. To explore the molecular mechanism of how lovastatin inhibits the growth of nasopharyngeal carcinoma, we examined the proteome of nasopharyngeal carcinoma cells treated at different time points using an LC/MS whole-proteomic strategy. The molecular network of differentially expressed proteins was constructed using IPA software. It was found that lovastatin inhibited the growth of nasopharyngeal carcinoma cells mainly by affecting the EIF2 and the mTOR pathways, which regulate cell metabolism and apoptosis. The results of this study provide a robust basis for further research on the molecular mechanism of lovastatin's inhibition of nasopharyngeal carcinoma cells and provide a reference for the clinical use of lovastatin in the treatment of nasopharyngeal carcinoma.

HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis.

Introduction: Transforming growth factor-beta (TGFß) signaling plays a vital role in lung adenocarcinoma (LUAD) progression. However, the involvement of TGFß-regulated long non-coding RNAs (lncRNAs) in metastasis of LUAD remains poorly understood. Methods: We performed bioinformatic analyses to identify putative lncRNAs regulated by TGF-ß/SMAD3 and validated the results by quantitative PCR in LUAD cells. We performed luciferase reporter and chromatin immunoprecipitation assays to demonstrate the transcriptional regulation of the lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) we decided to focus on. Stable HCP5 knockdown and HCP5-overexpressing A549 cell variants were generated respectively, to study HCP5 function and understand its mechanism of action. We also confirmed our findings in mouse xenografts and metastasis models. We analyzed the correlation between the level of lncRNA expression with EGFR, KRAS mutations, smoke state and prognostic of LUAD patients. Results: We found that the lncRNA HCP5 is induced by TGFß and transcriptionally regulated by SMAD3, which promotes LUAD tumor growth and metastasis. Moreover, HCP5 is overexpressed in tumor tissues of patients with LUAD, specifically in patients with EGFR and KRAS mutations and current smoker. HCP5 high expression level is positively correlated with poor prognosis of patients with LUAD. Finally, we demonstrated that upregulation of HCP5 increases the expression of Snail and Slug by sponging the microRNA-203 (miR-203) and promoting epithelial-mesenchymal transition (EMT) in LUAD cells. Conclusions: Our work demonstrates that the lncRNA HCP5 is transcriptionally regulated by SMAD3 and acts as a new regulator in the TGFß/SMAD signaling pathway. Therefore, HCP5 can serve as a potential therapeutic target in LUAD.

Long noncoding RNA CAR10 promotes lung adenocarcinoma metastasis via miR-203/30/SNAI axis.

Long noncoding RNAs (lncRNAs) play an important role in lung adenocarcinoma (LUAD) metastasis. Here, we found that lncRNA chromatin-associated RNA 10 (CAR10) was upregulated in the tumor tissue of patients with LUAD and enhanced tumor metastasis in vitro and in vivo. Mechanistically, CAR10 induced epithelial-to-mesenchymal transition (EMT) by directly binding with miR-30 and miR-203 and then regulating the expression of SNAI1 and SNAI2. CAR10 overexpression was positively correlated with a poor prognosis in LUAD patients, whereas overexpression of both CAR10 and SNAI was correlated with even worse clinical outcomes. In conclusion, the CAR10/miR-30/203/SNAI axis is a novel and potential therapeutic target for LUAD.

Redistributing the energy flow of a tightly focused radially polarized optical field by designing phase masks.

Redistributing the transverse energy flow in the focal plane of a tightly focused radially polarized optical field is described. We develop from theory a generalized analytical model for calculating the distributions of the electromagnetic field and the Poynting vector for a tightly focused radially polarized laser beam superposed with an optical vortex. We further explore the redistribution of the energy flow by designing phase masks, including traditional and annular vortex phase masks. Flexible control of the transverse energy flow rings is obtained with these phase masks. They provide a simple solution to transport absorptive particles along certain paths and therefore might be help in optical tweezer manipulations.

Focusing properties of arbitrary optical fields combining spiral phase and cylindrically symmetric state of polarization.

The tight focusing properties of optical fields combining a spiral phase and cylindrically symmetric state of polarization are presented. First, we theoretically analyze the mathematical characterization, Stokes parameters, and Poincaré sphere representations of arbitrary cylindrical vector (CV) vortex beams. Then, based on the vector diffraction theory, we derive and build an integrated analytical model to calculate the electromagnetic field and Poynting vector distributions of the input CV vortex beams. The calculations reveal that a generalized CV vortex beam can generate a sharper focal spot than that of a radially polarized (RP) plane beam in the focal plane. Besides, the focal size decrease accompanies its elongation along the optical axis. Hence, it seems that there is a trade-off between the transverse and axial resolutions. In addition, under the precondition that the absolute values between polarization order and topological charge are equal, a higher-order CV vortex can also achieve a smaller focal size than an RP plane beam. Further, the intensity for the sidelobe admits a significant suppression. To give a deep understanding of the peculiar focusing properties, the magnetic field and Poynting vector distributions are also demonstrated in detail. These properties may be helpful in applications such as optical trapping and manipulation of particles and superresolution microscopy imaging.

Optical cage generated by azimuthal- and radial-variant vector beams.

We propose a method to generate an optical cage using azimuthal- and radial-variant vector beams in a high numerical aperture optical system. A new kind of vector beam that has azimuthal- and radial-variant polarization states is proposed and demonstrated theoretically. Then, an integrated analytical model to calculate the electromagnetic field and Poynting vector distributions of the input azimuthal- and radial-variant vector beams is derived and built based on the vector diffraction theory of Richards and Wolf. From calculations, a full polarization-controlled optical cage is obtained by simply tailoring the radial index of the polarization, the uniformity U of which is up to 0.7748, and the cleanness C is zero. Additionally, a perfect optical cage can be achieved with U=1, and C=0 by introducing an amplitude modulation; its magnetic field and energy flow are also demonstrated in detail. Such optical cages may be helpful in applications such as optical trapping and high-resolution imaging.

Focus shaping by tailoring arbitrary hybrid polarization states that have a combination of orthogonal linear polarization bases.

We report a focus shaping method by tailoring hybrid states of polarization of arbitrary polarized beams that have a combination of orthogonal linear polarization bases. Such hybridly polarized beams comprising linear, elliptical, and circular polarizations in the beam cross section, have completely different optical properties compared to the scalar and locally linear-polarized vector beams. We demonstrate that, apart from the orientation of the local polarization state, another two degrees of freedom including the local ellipticity and the handedness in the beam cross section can be used in focus shaping. Square-shaped patterns, multiple foci, three-dimensional optical cages, optical needles, and channels can be obtained due to the increased control without any additional phase or amplitude modulations.

Fibroblasts play a potential role in bone destruction via osteopontin related caldesmon expression and polymerization in human non-functioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. The elucidation of the mechanisms of aggressive NFPAs in bone destruction is required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, we investigated the differential proteomics of fibroblasts isolated from clinical specimens of NFPAs with or without bone destruction. Proteomic analysis revealed a group of molecules associated with cytoskeleton organization, including caldesmon, were differentially expressed between fibroblasts isolated from bone destruction NFPAs (BD-NFPAs) and fibroblasts isolated from non-bone destruction NFPAs (NBD-NFPAs). The secreted proteins analysis found that osteopontin was significantly upregulated in BD-NFPAs fibroblasts. Furthermore, immunohistochemical staining of the NFPAs clinical samples showed that the expression of caldesmon in stromal cells and the expression of osteopontin in both tumor cells and stroma were significantly increased in BD-NFPAs. Taken together, our results indicate a possible way that osteopontin secreted from both NFPA cells and surrounding fibroblasts modify caldesmon expression and polymerization in fibroblasts, which may contribute to bone destruction in NFPA patients.

MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A.

MicroRNA expression profiling assays have shown that miR-34b/c and miR-449a are down-regulated in nasopharyngeal carcinoma (NPC); however, the targets and functions of miR-34b/c and miR-449a in the pathologenesis of NPC remain elusive. In this study, we verified miR-34b/c and miR-449a were significantly reduced with the advance of NPC. Overexpression of miR-34b-3 and miR-449a suppressed the growth of NPC cells in culture and mouse tumor xenografts. Using tandem mass tags for quantitative labeling and LC-MS/MS analysis to investigate protein changes after restoring expression of miR-34b-3, 251 proteins were found to be down-regulated after miR-34b-3 transfection. Through 3 replicate experiments, we found that miR-34b-3 regulated the expression of 15 potential targeted genes mainly clustered in the key enzymes of glycolysis metabolism, including lactate dehydrogenase A (LDHA). Further investigation revealed that miR-34b-3 and miR-449a negatively regulated LDHA by binding to the 3' untranslated regions of LDHA. Furthermore, LDHA overexpression rescued the miR-34b-3 and miR-449a induced tumor inhibition effect in CNE2 cells. In addition, miR-34b-3 and miR-449a suppressed LDH activity and reduced LD content, which were directly induced by downregulation of the LDHA. Our findings suggest that miR-34b-3 and miR-449a suppress the development of NPC through regulation of glycolysis via targeting LDHA and may be potential therapeutic targets for the treatment of NPC.