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Abstract Background The clinical response rate to immune checkpoint blockade (ICB) therapy in melanoma remains low, despite its widespread use. Circular non-coding RNAs (circRNAs) are known to play a crucial role in cancer progression and may be a key factor limiting the effectiveness of ICB treatment. Methods The circRNAs that were downregulated after coadministration compared with single administration of PD-1 inhibitor administration were identified through RNA-seq and Ribo-seq, and thus the circPIAS1 (mmu_circ_0015773 in mouse, has_circ_0008378 in human) with high protein coding potential was revealed. Fluorescence in situ hybridization (FISH) assays were conducted to determine the localization of circPIAS1 in human and mouse melanoma cells, as well as its presence in tumor and adjacent tissues of patients. Validation through dual-luciferase reporter assay and LC–MS/MS confirmed the ability of circPIAS1 to encode a novel 108 amino acid polypeptide (circPIAS1-108aa). Specific antisense oligonucleotides (ASOs) targeting the junction site of circPIAS1 were developed to reduce its intracellular levels. Proliferation changes in melanoma cells were assessed using CCK8, EdU, and colony formation assays. The impact of circPIAS1-108aa on the ferroptosis process of melanoma cells was studied through GSH, MDA, and C11-BODIPY staining assays. Western Blot, Immunoprecipitation (IP), and Immunoprecipitation-Mass Spectrometry (IP-MS) techniques were employed to investigate the impact of circPIAS1-108aa on the P-STAT1/SLC7A11/GPX4 signaling pathway, as well as its influence on the balance between STAT1 SUMOylation and phosphorylation. Additionally, a melanoma subcutaneous transplanted tumor mouse model was utilized to examine the combined effect of reducing circPIAS1 levels alongside PD-1 inhibitor. Results Compared with the group treated with PD-1 inhibitor alone, circPIAS1 was significantly down-regulated in the coadministration group and demonstrated higher protein coding potential. CircPIAS1, primarily localized in the nucleus, was notably upregulated in tumor tissues compared to adjacent tissues, where it plays a crucial role in promoting cancer cell proliferation. This circRNA can encode a unique polypeptide consisting of 108 amino acids, through which it exerts its cancer-promoting function and impedes the effectiveness of ICB therapy. Mechanistically, circPIAS1-108aa hinders STAT1 phosphorylation by recruiting SUMO E3 ligase Ranbp2 to enhance STAT1 SUMOylation, thereby reactivating the transduction of the SLC7A11/GPX4 signaling pathway and restricting the immunogenic ferroptosis induced by IFNγ. Furthermore, the combination of ASO-circPIAS1 with PD-1 inhibitor effectively inhibits melanoma growth and significantly enhances the efficacy of immune drugs in vivo. Conclusions Our study uncovers a novel mechanism regarding immune evasion in melanoma driven by a unique 108aa peptide encoded by circPIAS1 in melanoma that dramatically hinders immunogenic ferroptosis triggered by ICB therapy via modulating the balance between SUMOylation and phosphorylation of STAT1. This work reveals circPIAS1-108aa as a critical factor limiting the immunotherapeutic effects in melanoma and propose a promising strategy for improving ICB treatment outcomes.

The ion source is one of the key devices for the high-intensity cyclotron, which exerts influence on the beam intensity and applications of the machine. As part of the cyclotron research and development effort, China Institute of Atomic Energy (CIAE) has been developing arc discharge H- ion sources based on volume production and multi-cusp magnetic configuration since 1997. In 2000, 5.2 mA H- beam was reached and 15 mA H- beam was achieved in 2010. After a long break, H- ion source development started again in 2022 in order to improve performance of the main H- ion source of the CIAE 18 MeV cyclotron and to fulfill the requirement of future other high intensity proton beam cyclotrons for the high intensity H- ion. A new H- ion source and test stand was built at CIAE in 2023. The design of this new ion source was based on the experience on our previous 15-20 mA H- ion source and the source at TRIUMF. Major efforts included the study of the virtual filter magnetic field for filtering out fast electrons, multi-cusp confining magnetic field, four-half-circle ring filaments length and location, improvement of extraction structure and upgrading of vacuum system and power supplies. Up to now, more than 21 mA of H- beam were obtained at a high voltage of 35 kV from a plasma electrode hole of 13 mm in diameter when the hydrogen flux was 25 sccm. At this output the maximum arc power available is only 4.5 kW and the e/H- ratio is about 5. When the hydrogen flux is higher or extraction high voltage is higher, H- beam currents can reach 22 mA. However, the H- beam is very unstable with terrible sparks at extraction and acceleration gaps in this case, about five times a minute. This appears to be due to the lack of a differential pumping structure, which also results in an unexpectedly high hydrogen flux. In the experiment, the relationship between arc power and H- beam intensity was determined, also the optimal location of the four-filament structure was determined, which is obviously related to the virtual filter magnetic field distribution. At present, the emittance scanner is being processed and the measurement program is also updated and improved, the beam emittance has not been measured and analyzed at this stage. Subsequently, the vacuum chamber structure will be improved, the extraction structure also will be optimized to obtain brighter H- beam, and a long-lasting filament will be developed to reduce maintenance time.

IntroductionIncreased uncertainty is a major feature of the current society that poses significant challenges to university students' mental health and academics. However, current research has not paid sufficient attention to this issue, and no study has explored the underlying mechanisms between intolerance of uncertainty and academic burnout among university students.MethodsThis study examined the association between uncertainty intolerance and academic burnout among university students and the role of self-regulatory fatigue and self-compassion in light of the theory of limited resources. Convenience sampling was used to survey 1,022 Chinese university students.ResultsThe findings demonstrated that intolerance of uncertainty significantly influenced university students' academic burnout with self-regulatory fatigue serving as a key mediator. Additionally, self-compassion can effectively moderate the effects of intolerance of uncertainty on self-regulatory fatigue and academic burnout.DiscussionThese results indicated that the depletion of cognitive resources brought about by uncertainty in the current highly uncertain social environment may be one of the key pathways to academic burnout among university students. Furthermore, current research provides insights into how to mitigate the negative effects of uncertainty on university students.

IntroductionCurrent vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated.MethodsWe evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses.ResultsOur results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine.DiscussionOur findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice.

In recent years, cryotherapy has gained increasing acceptance as a treatment for prostate cancer, offering complementary therapeutic benefits when combined with radical surgery and radiotherapy. Despite the potential for surgical complications, it stands as a safe and viable therapeutic modality. Cryotherapy provides an efficient approach for elderly patients, especially those with compromised physical conditions and individuals experiencing recurrence after initial treatment. It has shown promise in extending survival periods and improving the overall quality of life for these patients. This article aims to comprehensively examine the developmental trajectory, surgical techniques, indications, therapeutic outcomes, and potential complications associated within prostate cancer treatment.

The Kangjiawan Pb-Zn deposit, situated within the Shuikoushan polymetallic ore field in Changning, Hunan Province, China, is a large-scale Pb-Zn deposit unearthed in 1976. Based on detailed geological field investigations, this study presents the results of the Rb-Sr isotopic dating, electron probe microanalyses (EPMAs), and LA-ICP-MS analyses of the Kangjiawan Pb-Zn deposit in order to determine the ore-forming age and the occurrence of trace elements in sphalerite and thereby constrain the genesis of the deposit. The Rb-Sr dating of quartz-hosted fluid inclusions yielded an Rb-Sr isochron age of 150 ± 4 Ma, with an initial 87Sr/86Sr ratio of 0.71101 ± 0.00008 (MSWD = 1.1), suggesting that the Pb-Zn mineralization of the Kangjiawan deposit took place during the Late Jurassic, coeval with the magmatic activities within the ore field. EPMA and LA-ICP-MS analyses showed that Fe, Mn, and Cd were primarily incorporated into the sphalerite lattice through isomorphous substitution. Specifically, Fe and Mn substituted for Zn, whereas Cd replaced both Fe and Zn. Other elements such as Cu, Sb, and Sn occurred within the sphalerite lattice through mineral micro-inclusions or isomorphic substitution. EPMAs and LA-ICP-MS results showed that the FeS contents in sphalerite were less than 14.33%, with corresponding ore-forming temperatures below 259 °C. The LA-ICP-MS results showed that sphalerites from the Kangjiawan Pb-Zn deposit had relatively high Ga/In ratios ranging from 0.01 to 144, providing further support for medium-to-low-temperature mineralization. The trace element compositions of sphalerites from the Kangjiawan Pb-Zn deposit exhibit skarn-type characteristics, suggesting a potential association with contemporary magmatic activities within the Shuikoushan ore field. During the Late Jurassic, extensive granitic magmatic activities occurred in the study area. At the late stage of magma crystallization, hydrothermal fluid containing Pb and Zn precipitated at medium-to-low temperatures and generated the Kangjiawan Pb-Zn deposit.

Objective： Optimized the drying process of jujube slices and improved the product quality. Methods： Taking jujube slices as the research object, the correlation between conversion moisture content, infrared temperature and slice thickness and drying time and drying rate was studied, and the change rule of effective moisture diffusion coefficient of jujube slices in FD-IRD with conversion moisture content, infrared temperature and slice thickness was calculated, and the drying activation energy of jujube slices in FD-IRD was calculated according to the test data. Results： The lower the conversion moisture content is, the shorter the infrared drying time was. But the lower the conversion moisture content would greatly increase the freeze drying time. Proper increase of infrared drying temperature was beneficial to increase the effective diffusion coefficient of water. The thinner the slice is, the higher the drying rate was. Reducing the slice thickness can improve the effective water diffusion coefficient and shorten the drying time. The front and rear two stages were both speeds reducing drying processes. The effective moisture diffusion coefficients of freeze-drying and infrared drying under different drying conditions by solving Fick's second law were 3.39×10-9~9.47×10-9 and 3.34×10-9~2.01×10-8 m2/s, respectively; The drying activation energy of the infrared drying stage was 59.03 kJ/mol calculated by Anius formula. Conclusion： The conversion moisture content is 30%, and the infrared temperature is 60 ℃. Under the condition of slice thickness of 6 mm, the freeze infrared combined drying technology has short drying time and high efficiency.