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Abstract Background An increasing number of orphan medicinal products (OMPs) are being included in social health insurance schemes, significantly improving access to medicines for patients with rare diseases. However, high-priced OMPs are still not covered, primarily due to health equity controversies and inadequate data systems required for economic evaluation. The aim of this study was to estimate the burden of drug expenditures and the size of the reimbursement budget required for high-priced OMPs from the perspectives of society and healthcare payers. Methods The study performed a budget impact analysis using data from multiple sources to estimate the reimbursement budget for high-priced OMPs in Chengdu, a densely populated metropolis in China. The budget analysis consisted of three main elements: the number of patients, the price of drugs, and the simulated policy scenario. By adjusting the combinations of these elements, the budget fluctuations for payers were estimated. Furthermore, the study predicted the budget trend for the next three years to validate its sustainability. Results The analysis indicated that 98 rare disease patients in Chengdu required high-priced OMPs in 2019. This suggested a projected budget of CNY 179 million for these patients without reimbursement policies, from a societal perspective. Under six assumed policy scenarios, this budget ranged from CNY 32 million to CNY 156 million. Over the next three years, the annual budget was estimated to range from CNY 200 million to CNY 1.303 billion. Conclusion Integration of multi-source data helps to obtain more scientifically reliable results on budget impacts. The study found that the budgetary impacts of high-priced OMPs on society and payers are relatively limited. Health policymakers can choose appropriate reimbursement strategies based on financial affordability among a diverse mix of elements. The results of related studies provided insights for optimizing the allocation of health resources and improving patient access to medications.

Abstract We have determined the crystal structure of a pseudoknot (PK)-containing hammerhead ribozyme that closely resembles the pistol ribozyme, with essentially identical secondary structure and connectivity. The activity is more sensitive to deletion of the G8 2’OH than to the absence of magnesium ions, indicating that the catalytic mechanism is the same as the extended hammerhead, and distinct from the pistol ribozyme. Here we show that nucleophilic attack is almost perfectly in-line, and the G8 2’OH is well positioned to act as general acid, being directed towards the O5’ leaving group, and 2.9 Å away from it. Despite the similarity in overall structure to the pistol ribozyme, the local structure close to the cleavage site differs, and the PK hammerhead retains its unique mechanistic identity and demonstrates enhanced activity over other hammerhead ribozymes under standard conditions.

BackgroundMaternal and perinatal health are fundamental to human development. However, in low-resource settings such as sub-Saharan Africa (SSA), significant challenges persist in reducing maternal, newborn, and child mortality. To achieve the targets of the sustainable development goal 3 (SDG3) and universal health coverage (UHC), improving access to continuous maternal and perinatal health care services (CMPHS) has been addressed as a critical strategy. ObjectiveThis study aims to provide a widely applicable procedure to illuminate the current challenges in ensuring access to CMPHS for women of reproductive age. The findings are intended to inform targeted recommendations for prioritizing resource allocation and policy making in low-resource settings. MethodsIn accordance with the World Health Organization guidelines and existing literature, and taking into account the local context of CMPHS delivery to women of reproductive age in Mozambique, we first proposed the identification of CMPHS as the continuum of 3 independent service packages, namely antenatal care (ANC), institutional delivery (ID), and postnatal care (PNC). Then, we used the nearest-neighbor method (NNM) to assess spatial access to each of the 3 service packages. Lastly, we carried out an overlap analysis to identify 8 types of resource-shortage zones. ResultsThe median shortest travel times for women of reproductive age to access ANC, ID, and PNC were 2.38 (IQR 1.38-3.89) hours, 3.69 (IQR 1.87-5.82) hours, and 4.16 (IQR 2.48-6.67) hours, respectively. Spatial barriers for women of reproductive age accessing ANC, ID, and PNC demonstrated large variations both among and within regions. Maputo City showed the shortest travel time and the best equity within the regions (0.46, IQR 0.26-0.69 hours; 0.74, IQR 0.47-1.04 hours; and 1.34, IQR 0.83-1.85 hours, respectively), while the provinces of Niassa (4.07, IQR 2.41-6.63 hours; 18.20, IQR 11.67-24.65 hours; and 7.69, IQR 4.74-13.05 hours, respectively) and Inhambane (2.69, IQR 1.49-3.91 hours; 4.43, IQR 2.37-7.16 hours; and 10.76, IQR 7.73-13.66 hours, respectively) lagged behind significantly in both aspects. In general, more than 51% of the women of reproductive age, residing in 83.25% of Mozambique’s land area, were unable to access any service package of CMPHS in time (within 2 hours), while only about 21%, living in 2.69% of Mozambique’s land area, including Maputo, could access timely CMPHS. ConclusionsThe spatial accessibility and equity of CMPHS in Mozambique present significant challenges in achieving SDG3 and UHC, especially in the Inhambane and Niassa regions. For Inhambane, policy makers should prioritize the implementation of a decentralization allocation strategy to increase coverage and equity through upgrading existing health care facilities. For Niassa, the cultivation of well-trained midwives who can provide door-to-door ANC and PNC at home should be prioritized, with an emphasis on strengthening communities’ engagement. The proposed 2-step procedure should be implemented in other low-resource settings to promote the achievement of SDG3.

Summary: The unfolded protein response (UPR) relieves endoplasmic reticulum (ER) stress through multiple strategies, including reducing protein synthesis, increasing protein folding capabilities, and enhancing misfolded protein degradation. After a multi-omics analysis, we find that signal recognition particle 14 (SRP14), an essential component of the SRP, is markedly reduced in cells undergoing ER stress. Further experiments indicate that SRP14 reduction requires PRKR-like ER kinase (PERK)-mediated eukaryotic translation initiation factor 2α (eIF2α) phosphorylation but is independent of ATF4 or ATF3 transcription factors. The decrease of SRP14 correlates with reduced translocation of fusion proteins and endogenous cathepsin D. Enforced expression of an SRP14 variant with elongation arrest capability prevents the reduced translocation of cathepsin D in stressed cells, whereas an SRP14 mutant without the activity does not. Finally, overexpression of SRP14 augments the UPR and aggravates ER-stress-induced cell death. These data suggest that translocational attenuation mediated by the PERK-SRP14 axis is a protective measure for the UPR to mitigate ER stress.

BackgroundDifferent kinds of mobile apps are used to promote communications between patients and doctors. Studies have investigated patients’ mobile app adoption behavior; however, they offer limited insights into doctors’ personal preferences among a variety of choices of mobile apps. ObjectiveThis study aimed to investigate the nuanced adoption behaviors among doctors in China, which has a robust adoption of mobile apps in health care, and to explore the constraints influencing their selection of specific mobile apps. This paper addressed 3 research questions: (1) Which doctors opt to adopt mobile apps to communicate with patients? (2) What types of mobile apps do they choose? (3) To what degree do they exercise personal choice in adopting specific mobile apps? MethodsWe used thematic content analysis of qualitative data gathered from semistructured interviews with 11 doctors in Hangzhou, which has been recognized for its advanced adoption of mobile technology in social services, including health care services. The selection of participants was purposive, encompassing diverse departments and hospitals. ResultsIn total, 5 themes emerged from the data analysis. First, the interviewees had a variety of options for communicating with patients via mobile apps, with the predominant ones being social networking apps (eg, WeChat) and medical platforms (eg, Haodf). Second, all interviewees used WeChat to facilitate communication with patients, although their willingness to share personal accounts varied (they are more likely to share with trusty intermediaries). Third, fewer than half of the doctors adopted medical platforms, and they were all from tertiary hospitals. Fourth, the preferences for in-person, WeChat, or medical platform communication reflected the interviewees’ perceptions of different patient cohorts. Lastly, the selection of a particular kind of mobile app was significantly influenced by the doctors’ affiliation with hospitals, driven by their professional obligations to fulfill multiple tasks assigned by the hospitals or the necessity of maintaining social connections with their colleagues. ConclusionsOur findings contribute to a nuanced understanding of doctors’ adoption behavior regarding specific types of mobile apps for patient communication, instead of addressing such adoption behavior of a wide range of mobile apps as equal. Their choices of a particular kind of app were positioned within a social context where health care policies (eg, limited funding for public hospitals, dominance of public health care institutions, and absence of robust referral systems) and traditional culture (eg, trust based on social connections) largely shape their behavioral patterns.

Summary: Background: High prices of anticancer drugs have raised concerns due to their financial impact on patients and healthcare systems. This study aimed to assess the initial and latest list prices and clinical value of reimbursed anticancer drugs in China, Japan, and South Korea. Methods: We identified anticancer drugs newly approved by the National Medical Products Administration of China from January 2012 to June 2022, and by the Pharmaceuticals and Medical Devices Agency of Japan and the Ministry of Food and Drug Safety of South Korea up until June 2022. We compared initial and latest treatment prices between countries and assessed clinical value using patients’ survival, quality of life (QoL), and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). We calculated Spearman rank correlation coefficients of treatment prices with clinical value for individual countries and employed regression analyses to investigate whether the relationship between prices and clinical value was modified by the country setting. Findings: Our cohort included 91 anticancer drug indications, with 60 listed for reimbursement in China, 91 in Japan, and 87 in South Korea. Median treatment prices were highest in Japan, followed by South Korea, and lowest in China, both for initial prices (US$64082 vs. US$45529 vs. US$19144, p

Abstract Biominerals, the inorganic minerals of organisms, are known mainly for their physical property-related functions in modern living organisms. Our recent discovery of the enzyme-like activities of nanomaterials, coined as nanozyme, inspires the hypothesis that nano-biominerals might function as enzyme-like catalyzers in cells. Here we report that the iron cores of biogenic ferritins act as natural nanozymes to scavenge superoxide radicals. Through analyzing eighteen representative ferritins from three living kingdoms, we find that the iron core of prokaryote ferritin possesses higher superoxide-diminishing activity than that of eukaryotes. Further investigation reveals that the differences in catalytic capability result from the iron/phosphate ratio changes in the iron core, which is mainly determined by the structures of ferritins. The phosphate in the iron core switches the iron core from single crystalline to amorphous iron phosphate-like structure, resulting in decreased affinity to the hydrogen proton of the ferrihydrite-like core that facilitates its reaction with superoxide in a manner different from that of ferric ions. Furthermore, overexpression of ferritins with high superoxide-diminishing activities in E. coli increases the resistance to superoxide, whereas bacterioferritin knockout or human ferritin knock-in diminishes free radical tolerance, highlighting the physiological antioxidant role of this type of nanozymes.

Abstract Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.

Abstract Background Healthy China is a nationwide health strategy aiming at improving health from diverse dimensions, and strengthening high-quality assessment is essential for its stimulation. However, there is limited evidence in the surveillance of the actual performance of the initiative at regional levels. This study innovatively proposes a two-step surveillance process which comprehensively monitors Healthy China Initiative based on regional realities, thus provides guidance for policymaking. Methods A flexible indicator system was firstly developed basing on Delphi survey and focus group discussions. And then the Analysis Hierarchical Process and the TOPSIS method were used to determine the weights of indicators and calculate comprehensive indexes as the surveillance outcomes. A pilot study was conducted in a typical area in China to verify the applicability of the process. Results Following the surveillance process and basing on the implementation of Healthy China Initiative in the target region, an indicator system comprised of 5 domains and 23 indicators with weights was first developed specifically for the pilot area. Then 1848 interagency data of the study area were collected from 8 provincial institutions/departments to calculate the indexes and ranks of the five domains which were health level, healthy living, disease prevention and control, health service, and healthy environment. The outcomes showed that Healthy China Initiative in the pilot area had been constantly improved since the strategy proposed, while there were still issues to be tackled such as the deficient monitoring mechanisms and unevenly development progress. Conclusions This study proposed a pragmatic surveillance process with indicators which could be tailored for specific context of target regions and produce meaningful surveillance outcomes to inform decision-making for policymakers, and also provided a theoretical foundation as well as empirical evidence for further health strategies and plannings assessment studies.

Retrogressive thaw slumps (RTS) are a form of abrupt permafrost thaw that can rapidly mobilize ancient frozen soil carbon, magnifying the permafrost carbon feedback. However, the magnitude of this effect is uncertain, largely due to limited information about the distribution and extent of RTS across the circumpolar region. Although deep learning methods such as Convolutional Neural Networks (CNN) have shown the ability to map RTS from high-resolution satellite imagery (≤10 m), challenges remain in deploying these models across large areas. Imagery selection and procurement remain one of the largest challenges to upscaling RTS mapping projects, as the user must balance cost with resolution and sensor quality. In this study, we compared the performance of three satellite imagery sources that differed in terms of sensor quality and cost in predicting RTS using a Unet3+ CNN model and identified RTS characteristics that impact detectability. Maxar WorldView imagery was the most expensive option, with a ground sample distance of 1.85 m in the multispectral bands (downloaded at 4 m resolution). Planet Labs PlanetScope imagery was a less expensive option with a ground sample distance of approximately 3.0–4.2 m (downloaded at 3 m resolution). Although PlanetScope imagery was downloaded at a higher resolution than WorldView, the radiometric footprint is around 10–12 m, resulting in less crisp imagery. Finally, Sentinel-2 imagery is freely available and has a 10 m resolution. We used 756 RTS polygons from seven sites across Arctic Canada and Siberia in model training and 63 RTS polygons in model testing. The mean IoU of the validation and testing data sets were 0.69 and 0.75 for the WorldView model, 0.70 and 0.71 for the PlanetScope model, and 0.66 and 0.68 for the Sentinel-2 model, respectively. The IoU of the RTS class was nonlinearly related to the RTS Area, showing a strong positive correlation that attenuated as the RTS Area increased. The models were better able to predict RTS that appeared bright on a dark background and were less able to predict RTS that had higher plant cover, indicating that bare ground was a primary way the models detected RTS. Additionally, the models performed less well in wet areas or areas with patchy ground cover. These results indicate that all imagery sources tested here were able to predict larger RTS, but higher-quality imagery allows more accurate detection of smaller RTS.

Abstract Background BAT1706 is a proposed biosimilar of bevacizumab, a vascular endothelial growth factor A (VEGF-A)-targeting biologic used to treat several different cancers, including metastatic colorectal cancer. A comprehensive physicochemical and functional similarity assessment is a key component of demonstrating biosimilarity between a reference biologic and a proposed biosimilar. Here we report the physicochemical and functional similarity of BAT1706 and reference bevacizumab sourced from both the United States (US-bevacizumab) and the European Union (EU-bevacizumab). Method A large range of product attributes, including primary and higher order structure, post-translational modifications, purity, stability, and potency, were characterized for BAT1706 and EU/US-bevacizumab using sensitive state-of-the-art analytical techniques. Up to 18 lots of US- and 29 lots of EU-bevacizumab, and 10 unique drug substance lots of BAT1706, were assessed. Result BAT1706 was shown to have an identical amino acid sequence and an indistinguishable higher-order structure compared with EU/US-bevacizumab. BAT1706 and EU/US-bevacizumab also exhibited similar post-translational modifications, glycan profiles, and charge variants. Potency, assessed using a wide range of bioassays, was also shown to be comparable between BAT1706 and EU/US-bevacizumab, with statistical equivalence demonstrated for VEGF-A binding and neutralizing activity. Conclusion Overall, this extensive comparability exercise demonstrated BAT1706 to match EU/US-bevacizumab in terms of all physicochemical and functional attributes assessed.

The Phenomena Identification and Ranking Table (PIRT) is a significant method for analyzing the safety of nuclear reactors. It helps researchers identify important phenomena within the reactor, enabling a focused and appropriate simplification of accident scenarios during the study. However, traditional PIRT methods often rely on experts' subjective opinions to rank phenomena’ importance and knowledge level, potentially distorting the PIRT results. This paper proposes a new PIRT method inspired by literature evaluation techniques used in the medical and healthcare field, which can be more objective. This new method utilizes a literature evaluation framework instead of relying solely on expert judgments, resulting in a more objective assessment of the phenomena’ importance and knowledge level. This study applies the new method to a simplified small modular reactor with a suppression containment system. Following a Loss of Coolant Accident (LOCA), the suppression containment can effectively suppress temperature and pressure increases, ensuring containment integrity. Relevant PIRT tables and a knowledge-level structure are obtained using the new method.

Abstract The success of arsenic in degrading PML‐RARα oncoprotein illustrates the great anti‐leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti‐cancer effects on solid tumors. A leukemia‐targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug significantly induces the differentiation of t(8;21) leukemia cells into more mature myeloid cells. Mechanistic analysis shows that the selenium is metabolized into bioactive forms in cells, which drives the degradation of the AML1‐ETO oncoprotein by inhibiting histone deacetylases activity, resulting in the regulation of AML1‐ETO target genes. The regulation results in a significant increase in the expression levels of myeloid differentiation transcription factors PU.1 and C/EBPα, and a significant decrease in the expression level of C‐KIT protein, a member of the type III receptor tyrosine kinase family. This study demonstrates that this protein‐nanocaged selenium is a potential therapeutic drug against t(8;21) leukemia through epigenetic regulation.

Abstract Nurses play a pivotal role in the delivery of medical services. Professional commitment is crucial for nursing professionals’ long-term, healthy, and sustainable development. However, nursing students’ professional commitment levels are currently unsatisfactory in China, especially given that the COVID-19 pandemic has posed unprecedented challenges to the profession. Therefore, studies investigating the professional commitment levels of nursing students and the underlying influencing factors are urgently required. This study explored how nursing students’ risk perceptions, negative emotions, and psychological capital affected their professional commitment during the COVID-19 pandemic. A cross-sectional study was conducted among nursing students using risk perception, professional commitment, negative emotions, and psychological capital scales. An analysis of 1142 Chinese nursing students suggested that nursing students’ risk perception positively impacted professional commitment and that negative emotions mediated this association. Importantly, psychological capital moderates the mediating effect of negative emotions and can buffer the negative emotions caused by risk perception. This study demonstrated that effective intervention strategies should be implemented in multiple dimensions such as education, individual, public and society to improve the professional commitment of nursing students.

This paper assesses trending AI foundation models, especially emerging computer vision foundation models and their performance in natural landscape feature segmentation. While the term foundation model has quickly garnered interest from the geospatial domain, its definition remains vague. Hence, this paper will first introduce AI foundation models and their defining characteristics. Built upon the tremendous success achieved by Large Language Models (LLMs) as the foundation models for language tasks, this paper discusses the challenges of building foundation models for geospatial artificial intelligence (GeoAI) vision tasks. To evaluate the performance of large AI vision models, especially Meta’s Segment Anything Model (SAM), we implemented different instance segmentation pipelines that minimize the changes to SAM to leverage its power as a foundation model. A series of prompt strategies were developed to test SAM’s performance regarding its theoretical upper bound of predictive accuracy, zero-shot performance, and domain adaptability through fine-tuning. The analysis used two permafrost feature datasets, ice-wedge polygons and retrogressive thaw slumps because (1) these landform features are more challenging to segment than man-made features due to their complicated formation mechanisms, diverse forms, and vague boundaries; (2) their presence and changes are important indicators for Arctic warming and climate change. The results show that although promising, SAM still has room for improvement to support AI-augmented terrain mapping. The spatial and domain generalizability of this finding is further validated using a more general dataset EuroCrops for agricultural field mapping. Finally, we discuss future research directions that strengthen SAM’s applicability in challenging geospatial domains.

Abstract Small water bodies (i.e., ponds; 0.01 km2). We leverage high‐resolution (3 m) optical satellite imagery from Planet Labs and deep learning methods to map seasonal changes in pond and lake areal extent across four regions in Alaska. Our water maps indicate that changes in open water extent over the snow‐free season are especially pronounced in ponds. To investigate potential impacts of seasonal changes in pond area on carbon emissions, we provide a case study of open water methane emission budgets using the new water maps. Our approach has widespread applications for water resources, habitat and land cover change assessments, wildlife management, risk assessments, and other biogeochemical modeling efforts.

The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.

Medical service pricing reform was considered as one of the focuses of China's remarkable health reform. This paper preliminarily assessed the roles of medical service pricing in the context of China's healthcare system. Specifically, we described the potential roles of medical service pricing in China and pointed out relevant challenges that emerged in practice as the result of reform-related activities. Multiple constraint factors that might have induced undesired outcomes were then recognized, including the excessive diversity and specialization of medical services, the price inelasticity of patients' demand, and the inadequate capability of both medical institutions and administrations. Finally, we provided policy recommendations to inform the ongoing medical service pricing reform in China from a long-term perspective.

Hospital infrastructure has been addressed as the prerequisite of healthcare delivery which intensively affects medical quality. Over the past decade, China has proposed a series of investment plans for hospital infrastructure in order to promote healthcare development in underdeveloped regions. Focusing on the construction of hospital buildings as the key component of hospital infrastructure, this study aims to examine whether the investment efficiency is lower where a government prioritizes equity and to explore what kind of geographical predispositions should be embedded in governmental investment plans for hospital infrastructures from the perspectives of both investment equity and efficiency. Relevant data from 330 governmental-invested hospital building construction projects in Sichuan province, China, from 2009 to 2018 were collected. Concentration index was used to evaluate the equity in the distribution of the investments. Tobit model was employed to explore the relationship between regional economic development and investment efficiency measured by an integrated approach of principal component analysis and data envelopment analysis. The results demonstrated a slight concentration of governmental investments in economically developed regions, while a negative association with regional economic development was identified with investment efficiency. Our study illustrated the investment efficiency was higher where a government prioritized equity and provided empirical evidences on switching governmental investment predisposition in the aspect of healthcare infrastructure construction toward less developed regions in China from the perspectives of both investment allocation equity and efficiency, which would further assist in the formulation of region-specific policies and strategies for underdeveloped regions.

The ubiquitin–proteasome system regulates a variety of cellular processes including growth, differentiation and apoptosis. While E1, E2, and E3 are responsible for the conjugation of ubiquitin to substrates, deubiquitinating enzymes (DUBs) reverse the process to remove ubiquitin and edit ubiquitin chains, which have profound effects on substrates’ degradation, localization, and activities. In the present study, we found that the deubiquitinating enzyme USP47 was markedly decreased in primary colorectal cancers (CRC). Its reduced expression was associated with shorter disease-free survival of CRC patients. In cultured CRC cells, knockdown of USP47 increased pyroptosis and apoptosis induced by chemotherapeutic doxorubicin. We found that USP47 was able to bind with transcription elongation factor a3 (TCEA3) and regulated its deubiquitination and intracellular level. While ectopic expression of USP47 increased cellular TCEA3 and resistance to doxorubicin, the effect was markedly attenuated by TCEA3 knockdown. Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.

Abstract Background We and others have previously shown that the STAT3 signaling pathway is activated in some esophageal squamous cell carcinoma (ESCC) cells and is required for the survival and growth of these primary ESCC-derived xenografts. It has also been shown that the natural polyphenol curcumin is an effective anti-tumor agent. Methods Luciferase assay and immunoblotting were performed to examine whether curcumin suppressed STAT3 signaling. CCK-8 assay and xenografts were utilized for analyzing ESCC cell growth in culture and mice. Soft agar assay was carried out to determine the colony formation ability of ESCC cells in the presence or absence of curcumin. Cell death and cell cycle were assessed by In CELL Analyzer 2000. Immunohistochemistry and TUNEL assay were used for detecting apoptosis in ESCC tisuses. Molecular docking was performed to evaluate the interaction of curcumin with JAK2. JAK2 activity was assessed using an in vitro cell-free system. HE staining was used to evaluate the ESCC tissues. Results The natural polyphenol curcumin inhibited STAT3 phosphorylation rapidly and blocked STAT3-mediated signaling in ESCC cells. It also induced growth arrest and apoptosis in cultured ESCC cells, which were attenuated by enforced expression of STAT3. Furthermore, curcumin preferentially blocked the growth of primary ESCC-derived xenografts that harbored activated STAT3. Conclusions Curcumin is able to exert anti-tumor action through inhibiting the STAT3 signaling pathway. Giving its wide use in traditional medicines with low toxicity and few adverse reactions, it is conceivable that curcumin might be further explored as a unique STAT3 inhibitor for anti-cancer therapies.

Mutations and altered expression of deubiquitinating enzymes (DUBs) have been found associated with many human diseases including cancers. In this study, Ubiquitin specific protease 1 (USP1) expression was found significantly increased in some colorectal cancers (CRC). The elevated USP1 level was associated with short overall survival of patients and with advanced stages of cancers. In cultured CRC cells, knockdown of USP1 induced growth arrest at G2/M of cell cycle and reduced the expression of anti-apoptotic proteins Bcl-2 and Mcl-1. Its knockdown also led to reduction of DNA-repair related substrates FANCD2 and ID1. Further investigations found that small molecular inhibitor of USP1 ML323 sensitized CRC cells to DNA-targeting chemotherapeutics, including doxorubicin, TOPI/II inhibitors, and PARP inhibitor, but not to 5-Fu. These results indicate that USP1 plays a critical in colorectal cancer cell survival and is a promising target for anti-colorectal cancer chemotherapy. Targeting USP1 may represent an effective strategy to regulate the DNA-repairing system.

The outbreak of coronavirus disease 2019 (COVID-19) has led to numerous tragic deaths all over the world. Great efforts have been made by worldwide nations for COVID-19 targeted vaccine development since the disease outbreak. In January 2021, the Chinese government started to provide free vaccination among nationwide communities, which was optional for citizens. As no evidence has been provided so far regarding COVID-19 vaccination acceptance since the initiation of nationwide vaccination, this study aims to investigate COVID-19 vaccination acceptance among Chinese citizens as well as its associated factors as an attempt to bridge such gap embedded in the current literature. An anonymous cross-sectional study was conducted online in March and April 2021 among adults, with the survey questionnaire designed based on the framework of the health belief model (HBM). Information on socio-demographics, risk perception, past pandemic-related experience, awareness of vaccination as well as acceptance of COVID-19 vaccination were collected. Chi-squared test and multi-level regression were performed to distinguish the acceptance between different groups as well as to identify the significant predictors. A total of 3940 participants completed the survey, with 90.6% of the participants reporting strong willingness to get vaccinated. A list of factors were found to be significantly associated with individuals’ acceptance of vaccination, including the region of residence, ethnicity, annual income, whether or not they had experienced a major pandemic event in the past, risk perception of the COVID-19 as well as the awareness of receiving vaccination. Safety concerns about the vaccine (27.7%), concerns about receiving vaccination immediately after newly developed vaccines were released into the market (22.4%) as well as concerns about the potential side effects induced by vaccination (22.1%) were identified as the primary reasons of residents’ resistance against vaccination. Overall, residents demonstrated strong willingness to receive vaccination against COVID-19 in China. However, the improvement of vaccination-related knowledge among Chinese residents should be highlighted as a critical strategy to facilitate the penetration of nationwide vaccination in order to ultimately achieve the establishment of herd immunity in China.

Understanding geospatial impacts of multi-sourced drivers on the tourism industry is of great significance for formulating tourism development policies tailored to regional-specific needs. To date, no research in China has explored the combined impacts of socioeconomic and environmental drivers on city-level tourism from a spatiotemporal heterogeneous perspective. We collected the total tourism revenue indicator and 30 potential influencing factors from 343 cities across China during 2008–2017. Three mainstream regressions and an emerging local spatiotemporal regression named the Bayesian spatiotemporally varying coefficients (Bayesian STVC) model were constructed to investigate the global-scale stationary and local-scale spatiotemporal nonstationary relationships between city-level tourism and various vital drivers. The Bayesian STVC model achieved the best model performance. Globally, eight socioeconomic and environmental factors, average wage (coefficient: 0.47, 95% credible intervals: 0.43–0.51), employed population (−0.14, −0.17–−0.11), GDP per capita (0.47, 0.42–0.52), population density (0.21, 0.16–0.27), night-time light index (−0.01, −0.08–0.05), slope (0.10, 0.06–0.14), vegetation index (0.66, 0.63–0.70), and road network density (0.34, 0.29–0.38), were identified to have nonlinear effects on tourism. Temporally, the main drivers might have gradually changed from the local macro-economic level, population density, and natural environment conditions to the individual economic level over the last decade. Spatially, city-specific dynamic maps of tourism development and geographically clustered influencing maps for eight drivers were produced. In 2017, China formed four significant city-level tourism industry clusters (hot spots, 90% confidence), the locations of which coincide with China’s top four urban agglomerations. Our local spatiotemporal analysis framework for geographical tourism data is expected to provide insights into adjusting regional measures to local conditions and temporal variations in broader social and natural sciences.

Liver metastasis is the most common form of metastatic colorectal cancers during the course of the disease. The global change in protein abundance in liver metastatic colorectal cancers and its role in metastasis establishment have not been comprehensively analyzed. In the present study, fresh-frozen tissue samples including normal colon/localized/liver metastatic CRCs from each recruited patient were analyzed by quantitative proteomics using a multiplexed TMT labeling strategy. Around 5000 protein groups were quantified from all samples. The proteomic profile of localized/metastatic CRCs varied greatly from that of normal colon tissues; differential proteins were mainly from extracellular regions and participate in immune activities, which is crucial for the chronic inflammation signaling pathways in the tumor microenvironment. Further statistical analysis revealed 47 proteins exhibiting statistical significance between localized and metastatic CRCs, of which FILI1P1 and PLG were identified for the first time in proteomic data, which were highly associated with liver metastasis in CRCs.

This paper proposes an ultrasonic measurement system based on least squares support vector machines (LS-SVM) for inline measurement of particle concentrations in multicomponent suspensions. Firstly, the ultrasonic signals are analyzed and processed, and the optimal feature subset that contributes to the best model performance is selected based on the importance of features. Secondly, the LS-SVM model is tuned, trained and tested with different feature subsets to obtain the optimal model. In addition, a comparison is made between the partial least square (PLS) model and the LS-SVM model. Finally, the optimal LS-SVM model with the optimal feature subset is applied to inline measurement of particle concentrations in the mixing process. The results show that the proposed method is reliable and accurate for inline measuring the particle concentrations in multicomponent suspensions and the measurement accuracy is sufficiently high for industrial application. Furthermore, the proposed method is applicable to the modeling of the nonlinear system dynamically and provides a feasible way to monitor industrial processes.

Blades act as key components for twin-blade planetary mixer; their geometric parameters (blade–blade clearance and helical angle) and two different rotating modes (counter-rotating mode and co-rotating mode) were investigated numerically via commercial software ANSYS Fluent 14.5 to reveal the effects on the power or torque consumption. The results indicate that decreasing the blade–blade clearance or increasing the helical angle increases the power consumption of the twin-blade planetary mixer. The proportionality constant of power curves depends on the geometry of the blades.

Background Although studies have provided the estimates of floods-diarrhoea associations, little is known about the lag effect, effect modification, and attributable risk. Based on Sichuan, China, an uneven socio-economic development province with plateau, basin, and mountain terrains spanning different climatic zones, we aimed to systematically examine the impacts of floods on diarrheal morbidity. Methods We retrieved information on daily diarrheal cases, floods, meteorological variables, and annual socio-economic characteristics for 21 cities in Sichuan from January 1, 2017 to December 31, 2019. We fitted time-series Poisson models to estimate the city-specific floods-diarrhoea relation over the lags of 0-14 days, and then pooled them using meta-analysis for cumulative and lag effects. We further employed meta-regression to explore potential effect modifiers and identify effect modification. We calculated the attributable diarrheal cases and fraction of attributable morbidity within the framework of the distributed lag model. Results Floods had a significant cumulative association with diarrhoea at the provincial level, but varied by regions and cities. The effects of the floods appeared on the second day after the floods and lasted for 5 days. Floods-diarrhoea relations were modified by three effect modifiers, with stronger flood effects on diarrhoea found in areas with higher air pressure, lower diurnal temperature range, or warmer temperature. Floods were responsible for advancing a fraction of diarrhoea, corresponding to 0.25% within the study period and 0.48% within the flood season. Conclusions The impacts imposed by floods were mainly distributed within the first week. The floods-diarrhoea relations varied by geographic and climatic conditions. The diarrheal burden attributable to floods is currently low in Sichuan, but this figure could increase with the exposure more intensive and the effect modifiers more detrimental in the future. Our findings are expected to provide evidence for the formulation of temporal- and spatial-specific strategies to reduce potential risks of flood-related diarrhoea. [ABSTRACT FROM AUTHOR]

A study discovered retinoic acid receptors and retinoic X receptors (RXRs), and revealed that retinoic acid particularly presents activation-induced apoptosis of T-cell hybridomas and antigen-specific removal of immature CD4+ CD8+ thymocytes from alpha beta T-cell receptor transgenic mice. RXRs can take part in the mechanism of apoptosis prevention, because all-trans-retinoic acid was about 10 times less potent than 9-cis-retinoic acid. RXRs may be involved in T-cell growth, since 9-cis-retinoic is a powerful negative controller of activation-induced T-cell apoptosis.

Background: We explored the dynamic expression of platelet-derived growth factor-D (PDGF-D) and phosphorylated platelet-derived growth factor receptor-β (p-PDGFR-β) after traumatic brain injury in rats to provide theoretical basis for selecting therapeutic target and intervention time after traumatic brain injury. Methods: This study prepared the weight drop/impact acceleration-induced traumatic brain injury (TBI) model in rats, including sham group and TBI groups at different observation time points (6 hours, 12 hours, 24 hours, 3 days, and 7 days after TBI). The dynamic expression of PDGF-D and p-PDGFR-β after TBI were detected by western blot and immunofluorescence staining. Results: The expression level of PDGF-D and p-PDGFR-β after TBI was detected by western blot. The PDGF-D level was increased (p < 0.05) 6 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). The p-PDGFR-β level was increased (p < 0.05) 12 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). PDGF-D and p-PDGFR-β in brain tissues were found by immunofluorescence in the perihematoma area 24 hours after TBI. Conclusions: This study revealed the expression phenomenon of PDGF-D and p-PDGFR-β after TBI in rats, suggesting that PDGF-D participates in the process of secondary brain injury after TBI through specific binding with PDGFR-β, which provides a theoretical basis for further research on selecting therapeutic targets and intervention times after TBI. [ABSTRACT FROM AUTHOR]

The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related death around the world. MicroRNAs (miRNAs) are small non-coding RNAs that often are abnormally expressed in tumors. Detection and quantitation of miRNAs may provide information for the screening and early diagnosis of CRC. OBJECTIVES: The objective of our study was to determine whether fecal microRNAs (miR-29a, miR-145, miR-223, miR-224) could be used as biomarkers for the screening and early diagnosis of colorectal cancer. METHODS: We carried out a retrospective analysis of the miRNAs in fecal samples from 80 CRC patients and 51 normal controls. The levels of 4 miRNAs (miR-29a, miR-145, miR-223, and miR-224) were quantitated using the SYBR Green miScript PCR system and 2-ΔΔCt method. RESULTS: Our data indicated that the expression levels of miR-29a (p < 0.001), miR-223 (p < 0.001) and miR-224 (p < 0.001) are significantly lower in feces from CRC patients than these from normal volunteers, whereas their miR-145 levels are not significantly different (p = 0.59). Interestingly, the level of miR-29a (p < 0.001) in feces from individuals with rectum cancer is also significantly higher than that from patients with colon cancer. CONCLUSION: There are reduced expression of miR-29a, miR-223, and miR-224 in the feces from the CRC patients, which could be an informative biomarker for screening and early diagnosis of CRC. [ABSTRACT FROM AUTHOR]

Schizophrenia patients exhibit a decreased ability to detect change in their auditory environment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detection. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30mg/kg) on deviance detection. Ketamine attenuated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant's N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 μg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day × 21 days, s.c.) or olanzapine (10 mg/kg/day × 21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs.Neuropsychopharmacology (2007) 32, 786–792. doi:10.1038/sj.npp.1301239; published online 25 October 2006 [ABSTRACT FROM AUTHOR]

The tumor suppressor p53 is tightly controlled at low levels in cells by constant ubiquitination and proteasomal degradation. In response to stresses, ubiquitination of p53 is inhibited through diverse pathways, depending on the nature of the stimulus and cell type. This leads to the accumulation and activation of p53, which induces cell cycle arrest and/or apoptosis to prevent cells from transformation. Many studies have indicated that defects of the p53 system are present in most, if not all, human tumor cells. Meanwhile, significant progress has been made in understanding the molecular mechanisms of p53 ubiquitination and the regulation of the p53 system. Therefore, it is possible now to consider targeting ubiquitination as a means to regulate and reactivate p53 in tumors. Emerging evidence suggests that inhibiting the E3 activity of Mdm2, blocking the interaction of p53 and Mdm2, and restoring the function of mutated p53 are potential effective strategies to kill certain tumor cells selectively. It is conceivable that new chemotherapeutic agents based on these studies will be generated in the not-so-distant future.Oncogene (2004) 23, 2096-2106. doi:10.1038/sj.onc.1207411 [ABSTRACT FROM AUTHOR]

Examines the role of tumor necrosis factor-alpha on the signalling components. Concentration of proteasome inhibitor lactacystin; Activation of N-terminal kinase; Inhibition of calpain-like protease activity.

Glioblastoma (GBM) is one of the most malignant brain tumours and, despite advances in treatment modalities, it remains largely incurable. Ca2+ regulation and dynamics play crucial roles in different aspects of cancer, but they have never been investigated in detail in GBM. Here, we report that spontaneous Ca2+ waves in GBM cells cause unusual intracellular Ca2+ ([Ca2+]i ) elevations (>1 µM), often propagating through tumour microtubes (TMs) connecting adjacent cells. This unusual [Ca2+]i elevation is not associated with the induction of cell death and is concomitant with overexpression of mitochondrial Ca2+ uniporter (MCU). We show that MCU silencing decreases proliferation and alters [Ca2+]i dynamics in U87 GBM cells, while MCU overexpression increases [Ca2+]i elevation in human astrocytes (HAs). These results suggest that changes in the expression level of MCU, a protein involved in intracellular Ca2+ regulation, influences GBM cell proliferation, contributing to GBM malignancy. [ABSTRACT FROM AUTHOR]

This paper studies the feasibility of applying the ultrasonic spectrum technique to the measurement of particle concentrations in multicomponent suspensions. A combination of the kernel partial least squares (KPLS) model and the interval selection methods is implemented to build the relationship between the ultrasonic spectra of the first reflected pulses and the particle concentrations. First of all, the interval selection methods are used to select optimal spectral interval(s) from full spectra. Then, the KPLS models with optimal spectral interval(s) are tuned, built and evaluated to obtain the optimal model. Finally, the optimal KPLS model is employed to measure the particle concentrations in the mixing process and its online prediction ability is evaluated. In comparison with the linear partial least squares (PLS) models, the optimal KPLS model shows the best performance. The results demonstrate that particle concentrations in multicomponent suspensions can be measured online by the ultrasonic spectrum technique, and the KPLS model with optimal spectral interval(s) shows the superiority in model calibration. [ABSTRACT FROM AUTHOR]

An abstract of the article "Expression and Evaluation of RING Finger Proteins," by Yili Yang and colleagues is presented.

Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor. [ABSTRACT FROM AUTHOR]