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Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.

Beam profile measurement via wire scanner is a semi-invasive method, which has advantage of less beam influence compared with a profile target, and is widely used in particle accelerator all over the world. Wire scanner is adopted to be applied to Shanghai High Repetition Rate X-ray Free Electron Laser aNd Extreme Light Facility (SHINE). For this purpose, a prototype of wire scanner composed of a wire target, a set of mechanical mechanism, a beam loss monitor and a set of electronics was designed and developed. A tungsten wire with an outer diameter of 20 μm was used as the wire target, and the safety of this tungsten wire was proved by thermal simulation. The beam loss monitor in the wire scanner prototype consists of a quartz fiber that generates Cherenkov light, and a photomultiplier tube. The data acquisition module was developed based on the ADQ14AC-4C data acquisition platform from Teledyne SP Devices, which is equipped with ADC chip with nominal bit of 14 bit, effective bit of about 9 bit, and analog 3 dB bandwidth of 1.2 GHz. The principle and specific design of the prototype were introduced in this paper. The optimization scheme of installing a cavity beam position monitor (CBPM) upstream of the wire target to accurately compensate the beam center position and the beam charge was also mentioned. In order to accurately evaluate performance of the prototype, we measured the beam profile simultaneously by arranging wire scanner system and a YAG target adjacent to each other in Shanghai Soft X-ray Free Electron Laser (SXFEL). The comparison of the experimental results show that the wire scanner can be used for the online semi-invasive beam profile measurement of the 0.84 GeV electron beam with a bunch charge of 500 pC. The resolustion of the prototype wire scanner is better than 30 μm, and especially less than 10 μm in the direction of low beam jitter. When the beam position changes greatly, the measurement accuracy of the prototype wire scanner is sharply improved by the CBPM system. Furthermore, the relative charge quantity calculated by the CBPM reference cavity signal is used to compensate the beam loss signal, and the measurement result of the prototype wire scanner is slightly improved. The results of the profile target agree with those of the prototype wire scanner well which verify the function of the device applied to SXFEL. The prototype of wire scanner system has laid a good technical foundation for SHINE construction, and at the same time, wire scanner system with CBPM can be used as a supplement for beam profile measurement in SXFEL.

Background and purposeCardiovascular disease associated with antiretroviral therapy (ART) has become a major clinical challenge for HIV-positive patients. However, the role of ART in blood vessel growth is largely unknown. Here, we examined an integral component of ART, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and investigated their effects on key microvascular functions, including angiogenesis and lymphangiogenesis.Experimental approachThe angiogenesis/lymphangiogenesis capability of endothelial cells (ECs) was evaluated using migration, proliferation and tube formation assays in vitro, and mouse ear and Matrigel plug assays in vivo. Expressions of signalling molecules and mitochondrial antioxidant catalases were determined using Western blotting. Receptor tyrosine kinase (RTK) internalization and endocytosis were examined using flow cytometry and confocal immunofluorescence microscopy respectively. Mitochondrial DNA copy number and ROS were determined using quantitative real-time PCR and MitoSOX staining respectively.Key resultsPharmaceutical doses of NRTIs [azidothymidine (AZT), tenofovir disoproxil fumarate (TDF) and lamivudine (3TC)] inhibited angiogenesis and lymphangiogenesis both in vivo and in vitro by affecting the proliferation and migration of ECs. Correspondingly, NRTIs selectively attenuated the activation and transduction of endothelial RTK signals, VEGFR2 and FGFR1 pathways, in vascular ECs and the VEGFR3 pathway in lymphatic ECs. Both TDF and 3TC restrained RTKs' endocytosis into early endosomes but not internalization, while AZT blocked the protein maturation of RTKs. Excessive ROS levels were detected in NRTI-treated ECs, and the MnSOD mimic MnTMPyP alleviated the angiogenic/lymphangiogenic defects induced by NRTIs.Conclusions and implicationsNRTIs negatively regulate angiogenesis and lymphangiogenesis by inducing mitochondrial oxidative stress and subsequently impairing RTK signalling in ECs.Linked articlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

This paper studies the optimal consumption, life insurance and investment problem for an income earner with uncertain lifetime under smooth ambiguity model. We assume that risky assets have unknown market prices that result in ambiguity. The individual forms his belief, that is, the distribution of market prices, according to available information. His ambiguity attitude, which is similar to the risk attitude described by utility function $ U $, is represented by an ambiguity preference function $ \phi $. Under the smooth ambiguity model, the problem becomes time-inconsistent. We derive the extended Hamilton-Jacobi-Bellman (HJB) equation for the equilibrium value function and equilibrium strategy. Then, we obtain the explicit solution for the equilibrium strategy when both $ U $ and $ \phi $ are power functions. We find that a more risk- or ambiguity-averse individual will consume less, buy more life insurance and invest less. Moreover, we find that the Tobin-Markowitz separation theorem is no longer applicable when ambiguity attitude is taken into consideration. The investment strategy will change with the characteristics of the decision maker, such as risk attitude, ambiguity attitude and age. [ABSTRACT FROM AUTHOR]

In order to better reduce the cost of e-commerce operations and save resources for marketing promotion, e-commerce merchants must adopt a reasonable and effective way to screen customers and improve the competitiveness of their own products. This paper takes the measurement of latent variable customer loyalty as the starting point, collects data through the design of questionnaires as the research basis, and uses Analysis of Moment Structure (AMOS) to construct structural equation model to conduct a validating factor analysis. It was found that the hypotheses proposed from the three subjects of business, customers themselves and logistics are all basically valid, and all three have a positive impact on loyalty. Ecommerce businesses should improve the service quality of their stores, ensure that their products can meet the needs of most customers, and build a good brand image, and should also carefully choose logistics companies that are reliable and new to customers to cooperate with.

This paper focuses on the state estimation problem for a class of switching complex dynamical networks (CDNs) with unknown nonlinear dynamics. A novel neural network based (NN-based) state estimator with non-fragility is constructed to fulfill the state estimation task. In order to improve the efficiency of communication resource utilization, an event-triggered mechanism is applied in designing the estimator. By employing the Lyapunov stability theory and inequality technique, sufficient criteria are derived for the existence of the desired exponentially ultimately bounded NN-based state estimator for CDNs. It is also proven that the proposed event-triggered mechanism can avoid Zeno phenomenon. In addition, the gains of the desired estimators are characterized by the explicit expressions. Finally, the effectiveness of the proposed NN-based state estimator is verified by a simulation example. [ABSTRACT FROM AUTHOR]