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Abstract Since the Qin terracotta warriors were unearthed, polyamide 650 cross-linked E-44 epoxy resin binder has been employed to bond and restore them. In this paper, the chemical aging of the binders service in indoor natural environment during the past 30 years in the terracotta warriors was studied by means of infrared spectroscopy, X-ray photoelectron spectroscopy and thermogravimetric analysis. The results indicated that the binders did not emerge the characteristic peak of carbonyl stretching vibration at 1700 cm−1 in the IR spectra of all determined binders, and their thermal decomposition curves did not emerge any abnormal changes, and the thermal decomposition mainly occurred above 300 °C. There are evident ceramic grains attached to the surface of the binders being peeled off for sampling. These results that the binders service in the Qin terracotta warriors did not exhibit an observable chemical aging and still has strong adhesion. Generally, discrepancies were observed between natural aging and accelerated artificial aging due to the ineffectiveness of the latter to reproduce the effects of complex weather conditions. Compared to artificially accelerated aging, the evaluation results in a long-term natural aging of the binder which is used for restoration of the life-size Qin terracotta warriors, providing in the present investigation, are more reliable in terms of predicting the safety of restored terracotta warriors.

Abstract Background β-catenin, acting as the core effector of canonical Wnt signaling pathway, plays a pivotal role in controlling lineage commitment and the formation of definitive endoderm (DE) during early embryonic development. Despite extensive studies using various animal and cell models, the β-catenin-centered regulatory mechanisms underlying DE formation remain incompletely understood, partly due to the rapid and complex cell fate transitions during early differentiation. Results In this study, we generated new CTNNB1-/- human ES cells (hESCs) using CRISPR-based insertional gene disruption approach and systematically rescued the DE defect in these cells by introducing various truncated or mutant forms of β-catenin. Our analysis showed that a truncated β-catenin lacking both N- and C-terminal domains (ΔN148C) could robustly rescue the DE formation, whereas hyperactive β-catenin mutants with S33Y mutation or N-terminal deletion (ΔN90) had limited ability to induce DE lineage. Notably, the ΔN148C mutant exhibited significant nuclear translocation that was positively correlated with successful DE rescue. Transcriptomic analysis further uncovered that two weak β-catenin mutants lacking the C-terminal transactivation domain (CTD) activated primitive streak (PS) genes, whereas the hyperactive β-catenin mutants activated mesoderm genes. Conclusion Our study uncovered an unconventional regulatory function of β-catenin through weak transactivation, indicating that the levels of β-catenin activity determine the lineage bifurcation from mesendoderm into endoderm and mesoderm.

Abstract The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype–phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10–3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10–131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype–phenotype screens in diverse populations.

Background: Diabetic foot is a major complication of diabetes. The bone transverse transport method could be applied in clinics for treatment, which could improve the metabolism of the tissues via lasting distraction forces. However, the process’ specific regulating mechanism is still unknown. Methods: Based on the notion that the healing of bones involves the recruitment of calcium ions, in this study, we established the model of tibial cortex transverse transport (TTT) on rats and then used tissue immunologic detection, such as the double fluorescent staining to explore the expression of the calcium channels’ calcium release-activated calcium modulator 1 (Orai1)/stromal interaction molecule 1 (STIM1), which belong to the store-operated calcium entry (SOCE) signaling pathways on the tissues around the bone transport area. By using the laser capture microdissection (LCM) tool, we acquired samples of tissues around the bone and endeavored to identify pivotal protein molecules. Subsequently, we validated the functions of key protein molecules through in vitro and in vivo experiments. Results: After protein profile analysis, we found the differentially expressed key protein osteopontin (OPN). The in vitro experiments verified that, being stimulated by OPN, the migration, proliferation, and angiogenesis of human umbilical vein endothelial cells (HUVEC) were observed to be enhanced. The activation of Orai1/STIM1 might increase the activity of endothelial nitric oxide synthase (eNOS) and its effect on releasing nitric oxide (NO). Subsequently, the migration and proliferation of the HUVECs are improved, which ultimately accelerates wound healing. These signaling pathway was also observed in the OPN-stimulated healing process of the skin wound surface of diabetic mice. Conclusion: This study identifies the molecular biological mechanism of OPN-benefited the migration and proliferation of the HUVECs and provides ideas for searching for new therapeutic targets for drugs that repair diabetes-induced wounds to replace invasive treatment methods. The translational potential of this article: The OPN is highly expressed in the tissues surrounding the TTT bone transfer area, which may possibly stimulate the activation of eNOS to increase NO release through the SOCE pathway mediated by Orai1/STIM1. This mechanism may play a significant role in the angiogenesis of diabetic foot's wounds promoted by TTT, providing new therapeutic strategies for the non-surgical treatment for this disease.

Background: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. Methods: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE−/− mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE−/− mice. Results: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE−/− mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE−/− mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. Conclusions: Upon HCD feeding in ApoE−/− mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.

IntroductionChronic schizophrenia has a course of 5 years or more and has a widespread abnormalities in brain functional connectivity. This study aimed to find characteristic functional and structural changes in a long illness duration chronic schizophrenia (10 years or more).MethodsThirty-six patients with a long illness duration chronic schizophrenia and 38 healthy controls were analyzed by independent component analysis of brain network functional connectivity. Correlation analysis with clinical duration was performed on six resting state networks: auditory network, default mode network, dorsal attention network, fronto-parietal network, somatomotor network, and visual network.ResultsThe differences in the resting state network between the two groups revealed that patients exhibited enhanced inter-network connections between default mode network and multiple brain networks, while the inter-network connections between somatomotor network, default mode network and visual network were reduced. In patients, functional connectivity of Cuneus_L was negatively correlated with illness duration. Furthermore, receiver operating characteristic curve of functional connectivity showed that changes in Thalamus_L, Rectus_L, Frontal_Mid_R, and Cerebelum_9_L may indicate a longer illness duration chronic schizophrenia.DiscussionIn our study, we also confirmed that the course of disease is significantly associated with specific brain regions, and the changes in specific brain regions may indicate that chronic schizophrenia has a course of 10 years or more.

Abstract Semi-exposed relics within an air–soil system often have earthworks partially buried, leading to moisture migration and substantial salt accumulation. Salt accumulation threatens relic preservation, but destructive sampling is hindered by conservation concerns. We conducted a case study on salt enrichment at K9901 Armour Pit of Emperor Qinshihuang 's Mausoleum Site Museum. Environmental factors and soil salt characteristics were assessed through sampling and monitoring. A relic-soil coupling system was established with a soil column device containing burned bricks. Using 5-TE sensors, water and salinity movement was tracked, and X-ray diffraction analyzed relic salt crystals. The soil column experiment effectively simulated water-salt migration in relics. Salts, like Cl−, NO3 −, SO4 2−, Na+, and Mg2+, concentrated on the soil surface during evaporation. Simulation linked specific salt species to relic ailments. Salt solution from soil migrated to bricks, forming CaSO4 crystals. Results highlight coupling's role in salt-related deterioration and the need to protect it for optimal relic preservation. Findings impact semi-exposed relic conservation, revealing salt accumulation processes and their impact on historical artifacts.

Background: Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose: Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods: PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results: Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P

E-wallet, also referred to as digital wallet, is a software application designed to replace physical wallets, with the primary purpose of facilitating online transactions when users wish to make virtual payments. Nowadays, E-wallets are not limited to mobile applications, but they have also been extended to wearable devices, such as smartwatches, enabling users to make payments via their watches. This research study focuses on three main E-wallet service providers in Malaysia, namely TouchNGo E-wallet, Boost, and Grab pay, as they are the top three E-wallets in the country. The aim of this paper is to explore the real-world implementation of E-wallets among mobile phone users in Malaysia, employing the Technology Adoption Model as the theoretical framework. Six independent variables were identified to study the implementation of E-wallets, and a total of 500 respondents shared their opinions on retaining the usage of E-wallet in Malaysia. The data collected were analysed using SPSS for Pearson Correlation Analysis and Multiple Linear Regression. Out of the six variables, five independent variables were accepted, and one independent variable was rejected due to the greater significant level. The highest correlation coefficient falls under Business Resources with 0.704. The study delves into the implications and constraints, providing insights for the future advancement of E-wallets within the Malaysian context.

Abstract Background Multiple myeloma remains incurable despite treatment advancements over the last 20 years. LCAR-B38M Cells in Treating Relapsed/Refractory Multiple Myeloma was a phase 1, first-in-human, investigator-initiated study in relapsed/refractory multiple myeloma conducted at four sites in China. The study used LCAR-B38M chimeric antigen receptor-T cells expressing two B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity, and a CD3ζ signaling domain with a 4-1BB costimulatory domain to optimize T-cell activation and proliferation. This chimeric antigen receptor construct is identical to ciltacabtagene autoleucel. In the LEGEND-2 study (n = 57, Xi’an site), overall response rate was 88%; median (95% CI) progression-free survival and overall survival were 19.9 (9.6–31.0) and 36.1 (26.4–not evaluable) months, respectively; and median follow-up was 25 months. This case study reports on a patient with relapsed/refractory multiple myeloma (λ light chain type) who was treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study (Xi’an site); he had received five prior lines of treatment and had extensive extramedullary lesions. Case presentation The patient, a 56-year-old Asian male, received cyclophosphamide (500 mg daily × 3 days) as lymphodepletion therapy and a total dose of 0.5 × 106 chimeric antigen receptor + T cells/kg split into three infusions (days 1, 24, and 84 from June to August 2016). He experienced grade 2 cytokine release syndrome after the first infusion; all symptoms resolved with treatment. No cytokine release syndrome occurred following the second and third infusions. His λ light chain levels decreased and normalized 20 days after the first infusion, and extramedullary lesions were healed as of January 2018. He has sustained remission for 5 years and received no other multiple myeloma treatments after LCAR-B38M chimeric antigen receptor T cell infusion. As of 30 October 2020, the patient is still progression-free and has maintained minimal residual disease-negative (10–4) complete response status for 52 months. Conclusions This case provides support that treatment with LCAR-B38M chimeric antigen receptor T cells can result in long-term disease remission of 5 or more years without disease progression in a heavily pretreated patient with extensive extramedullary disease and no other treatment options.

Abstract Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

Abstract BRCA1 and BRCA2 mutation carriers face an elevated lifetime risk of developing ovarian cancer. Oral contraceptives have been shown to significantly decrease the risk of ovarian cancer by approximately 50% in this high-risk population. Changes in contraceptive formulations and patterns of use over time have introduced lower hormonal dosages, different steroid types and non-oral routes of administration. Specifically, there has been a considerable shift in patterns of contraceptive use and the increase in the uptake of non-oral, long-acting, reversible contraception (e.g., intrauterine devices, implants, injections) has corresponded to a decline in oral contraceptive pill use. Whether or not these other methods confer a protective effect against ovarian cancer in the general population is not clear. To our knowledge, there have been no such studies conducted among BRCA mutation carriers. Furthermore, the impact of these changes on the risk of developing ovarian cancer is not known. In this article, we will review the existing epidemiologic evidence regarding the role of contraceptives and the risk of ovarian cancer with a focus on women with a BRCA1 or BRCA2 mutation. We will discuss recent findings and gaps in the knowledge while extrapolating from studies conducted among women from the noncarrier population.

BackgroundRenal fibrosis is the final common pathway of chronic kidney disease (CKD), which is clinically irreversible and without effective therapy. Renal tubules are vulnerable to various insults, and tubular injury is involving in the initiation and evolution of renal inflammation and fibrosis. Neurokinin-1 receptor (NK-1R) functions by interacting with proinflammatory neuropeptide substance P (SP), exerting crucial roles in various neurological and non-neurological diseases. However, its roles in renal inflammation and fibrosis are still unknown.MethodsWe collected renal biopsy specimens and serum samples of individuals with or without CKD. Additionally, knockout mice lacking NK-1R expression, SP addition and NK-1R pharmacological antagonist treatment in the unilateral ureteral obstruction (UUO) model, and NK-1R-overexpressed HK-2 cells were employed.ResultsRenal SP/NK-1R and serum SP were increased in patients with CKD and mice experiencing UUO and correlated with renal fibrosis and function. SP addition enhanced UUO-induced progressive inflammatory responses and renal fibrosis, whereas genetically or pharmacologically targeting NK-1R attenuated these effects. Mechanistically, TFAP4 promoted NK-1R transcription by binding to its promoter, which was abolished by mutation of the binding site between TFAP4 and NK-1R promoter. Furthermore, SP acted through the NK-1R to activate the JNK/p38 pathways to modulate cell fate of tubular epithelial cells including growth arrest, apoptosis, and expression of profibrogenic genes.ConclusionOur data reveals that SP/NK-1R signaling promotes renal inflammatory responses and fibrosis, suggesting NK-1R could be a potential therapeutic target for the patients with CKD.

This paper presents the design of a high-intensity 10 mA deuteron RFQ accelerator that generates a 2.1 MeV beam in a continuous wave (CW) mode. The operation frequency is 162.5 MHz. The results of beam dynamics simulations demonstrate excellent output beam quality, achieving a transmission efficiency of 98.63%. The beam tracking results indicate that the RFQ is capable of managing errors within reasonable tolerances. In addition, the RF electromagnetic design and optimization are based on an RFQ model. Multiphysics simulations are then performed for the CW mode. Vacuum calculations suggest that the RFQ requires four 1200 L/s vacuum pumps and one 440 L/s ion pump to attain a vacuum pressure of 10−6 Pa.

Abstract We study the competition between the p-wave and the p+ip superfluid solutions in a holographic model with applied magnetic field intensity H. We find that when H is turned on, both the grand potential and the critical temperature of the p+ip solution are shifted, while the p-wave solution is only slightly affected. Combining the effect of H and back reaction parameter b, we build H − T phase diagrams with a slit region of p+ip phase. The zero (or finite) value of H at the starting point of the slit region is related to second (or first) order of the p-wave phase transition at zero magnetic intensity, which should be universal in systems with degenerate critical points (spinodal points) at zero magnetic field.

Digital technologies are playing an increasing role in the global response to tuberculosis (TB), however their effectiveness and impact are often shaped in the context in which they are implemented. Implementation research can help facilitate the effective introduction of digital health technologies in TB programmes. In 2020, the Implementation Research for Digital Technologies and TB online toolkit (IR4DTB) was developed and launched by the Special Programme for Research and Training in Tropical Diseases, and the Global TB Programme at the World Health Organization (WHO), to build local capacity for IR and promote the effective use of digital technologies within TB programmes. This paper describes the development and piloting of the IR4DTB toolkit, a self-learning tool designed for TB programme implementers. The toolkit comprises six modules reflecting key steps of the IR process, practical instructions and guidance on how to complete these steps, and real-word case studies to illustrate key learning points. This paper also describes the launch of the IR4DTB during a five-day training workshop with TB staff from China, Uzbekistan, Pakistan, Malaysia. The workshop included facilitated sessions on the IR4DTB modules, and provided an opportunity for participants to work with facilitators to develop a comprehensive IR proposal addressing an identified challenge related to the implementation and/or scale-up of digital health technologies for TB care in their home country. Post-workshop evaluation revealed high level of satisfaction among participants with the workshop content and format. The IR4DTB toolkit is a replicable model which can be used to strengthen the TB staff capacity to innovate within a culture of continuous collection of evidence. Through continued trainings and adaptation of the toolkit alongside the integration of digital technologies within TB prevention and care, this model has the potential to contribute directly to all components of the End TB Strategy.