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Summary: Background: This study explores the potential of the deep learning-based convolutional neural network (CNN) to automatically recognize MMD using MRA images from atherosclerotic disease (ASD) and normal control (NC). Methods: In this retrospective study in China, 600 participants (200 MMD, 200 ASD and 200 NC) were collected from one institution as an internal dataset for training and 60 from another institution were collected as external testing set for validation. All participants were divided into training (N = 450) and validation sets (N = 90), internal testing set (N = 60), and external testing set (N = 60). The input to the CNN models comprised preprocessed MRA images, while the output was a tripartite classification label that identified the patient's diagnostic group. The performances of 3D CNN models were evaluated using a comprehensive set of metrics such as area under the curve (AUC) and accuracy. Gradient-weighted Class Activation Mapping (Grad-CAM) was used to visualize the CNN's decision-making process in MMD diagnosis by highlighting key areas. Finally, the diagnostic performances of the CNN models were compared with those of two experienced radiologists. Findings: DenseNet-121 exhibited superior discrimination capabilities, achieving a macro-average AUC of 0.977 (95% CI, 0.928–0.995) in the internal test sets and 0.880 (95% CI, 0.786–0.937) in the external validation sets, thus exhibiting comparable diagnostic capabilities to those of human radiologists. In the binary classification where ASD and NC were group together, with MMD as the separate group for targeted detection, DenseNet-121 achieved an accuracy of 0.967 (95% CI, 0.886–0.991). Additionally, the Grad-CAM results for the MMD, with areas of intense redness indicating critical areas identified by the model, reflected decision-making similar to human experts. Interpretation: This study highlights the efficacy of CNN model in the automated diagnosis of MMD on MRA images, easing the workload on radiologists and promising integration into clinical workflows. Funding: National Natural Science Foundation of China, Tianjin Science and Technology Project and Beijing Natural Science Foundation.

Abstract Purposes Radiotherapy can induce tumor cell autophagy, which might impair the antitumoral effect. This study aims to investigate the effect of autophagy inhibition on the targeted radionuclide therapy (TRT) efficacy of 131I-FAP-2286 in pancreatic cancer. Methods Human pancreatic cancer PANC-1 cells were exposed to 131I-FAP-2286 radiotherapy alone or with the autophagy inhibitor 3-MA. The autophagy level and proliferative activity of PANC-1 cells were analyzed. The pancreatic cancer xenograft-bearing nude mice were established by the co-injection of PANC-1 cells and pancreatic cancer-associated fibroblasts (CAFs), and then were randomly divided into four groups and treated with saline (control group), 3-MA, 131I-FAP-2286 and 131I-FAP-2286 + 3-MA, respectively. SPECT/CT imaging was performed to evaluate the bio-distribution of 131I-FAP-2286 in pancreatic cancer-bearing mice. The therapeutic effect of tumor was evaluated by 18F-FDG PET/CT imaging, tumor volume measurements, and the hematoxylin and eosin (H&E) staining, and immunohistochemical staining assay of tumor tissues. Results 131I-FAP-2286 inhibited proliferation and increased the autophagy level of PANC-1 cells in a dose-dependent manner. 3-MA promoted 131I-FAP-2286-induced apoptosis of PANC-1 cells via suppressing autophagy. SPECT/CT imaging of pancreatic cancer xenograft-bearing nude mice showed that 131I-FAP-2286 can target the tumor effectively. According to 18F-FDG PET/CT imaging, the tumor growth curves and immunohistochemical analysis, 131I-FAP-2286 TRT was capable of suppressing the growth of pancreatic tumor accompanying with autophagy induction, but the addition of 3-MA enabled 131I-FAP-2286 to achieve a better therapeutic effect along with the autophagy inhibition. In addition, 3-MA alone did not inhibit tumor growth. Conclusions 131I-FAP-2286 exposure induces the protective autophagy of pancreatic cancer cells, and the application of autophagy inhibitor is capable of enhancing the TRT therapeutic effect.

This study aims to assess and analyze the urban food resilience of the Zhengzhou metropolitan area, proposing innovative assessment frameworks and methodologies. Utilizing a dual-level analysis approach that combines long-term planning impact analysis (2000–2020) with short-term resilience assessment (2018–2022), the study integrates public government data and Geographic Information System (GIS) data, employing spatial analysis, Analytic Hierarchy Process (AHP), and fuzzy comprehensive evaluation techniques. Findings from 2000 to 2020 indicate that urban planning within the metropolitan area has significantly impacted the food system. Urbanization has led to reduced agricultural land, but improvements in infrastructure have enhanced the efficiency of the food supply chain. Woodland and grassland areas have remained relatively stable, providing an ecological buffer for the food system. Building on this, the short-term assessment from 2018 to 2022 reveals significant dynamic changes and a continuous improvement trend in food resilience, though there is still room for enhancement. Food supply chain management and emergency preparedness and management contributed the most to overall resilience. Notably, extreme events such as the COVID-19 pandemic and the “7.20 Flood Disaster” prompted the adoption of innovative measures to enhance food resilience. The study develops a multidimensional theoretical framework and assessment system for urban food resilience, offering new perspectives and methods for understanding and enhancing urban food resilience. The results highlight the critical role of urban planning in enhancing food resilience, recommending the integration of the food system into comprehensive urban planning, strengthening regional collaboration, and enhancing public engagement. These findings provide an important basis for policymaking and practice aimed at improving the long-term adaptability and short-term recovery capabilities of urban food systems.

Abstract Background Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs instrumental in ATR activation remain largely unclear, which limits our comprehensive understanding of this critical biological process. Methods RNA immunoprecipitation (RIP) followed by RNA sequencing was employed to identify ATR-binding lncRNAs, which were further validated using RIP-qPCR assays. Immunofluorescence staining and Western blotting were applied to detect the activation of DNA damage repair factors. After the effect of scaRNA2 on cellular sensitivity to DNA-damaging reagents was determined, the effects of scaRNA2 on radiotherapy were investigated in patient-derived organoids and xenograft preclinical models. The clinical relevance of scaRNA2 was also validated in tissues isolated from rectal cancer patients. Results ScaRNA2 was identified as the most enriched ATR-binding lncRNA and was found to be essential for homologous recombination (HR) mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the recruitment of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Knockdown of scaRNA2 effectively increased the sensitivity of cancer cells to multiple kinds of DNA damage-related chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the effects of radiotherapy on patient-derived organoids and xenograft models. Finally, an increase in scaRNA2 colocalized with ATR was also found in clinical patients who were resistant to radiotherapy. Conclusions ScaRNA2 was identified as the most abundant lncRNA bound to ATR and was demonstrated to bridge DNA end resection to ATR activation; thus, it could be applied as a potent target for combined cancer treatments with chemoradiotherapy.

Abstract Background Neoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers. Methods Through high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application. Results We identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy. Conclusion Our findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy.

Quantum sensing is a quantum technology for ultrasensitive detection, which is particularly useful for sensing weak signals at the nanoscale. Nitrogen vacancy centers in diamond, thanks to their superb quantum coherence under ambient conditions and the stability of the material in extreme and complicated environments, have been demonstrated as promising quantum probes in multi-parameter sensing. Their spin properties make them particularly sensitive to magnetic fields, but they are insensitive to temperature, electric field, pressure, etc., and even immune to some bio-parameters (e.g., pH and glucose concentration). Recently, hybrid quantum sensing has emerged as a promising avenue for further enhancing the capabilities of diamond sensors. Different techniques can potentially improve the sensitivity, range of detectable parameters, and sensing frequencies of diamond sensors. This review provides an overview of hybrid quantum sensing using diamond. We first give a brief introduction to quantum sensing using diamond, and then review various hybrid sensing schemes that have been developed to enhance the sensing capabilities of diamond sensors. Finally, the potential applications and challenges associated with hybrid quantum sensing in diamond are discussed.

INTRODUCTION: With the advent of the information technology era, rural areas face new environmental protection challenges and opportunities. The rapid development of information technology provides new possibilities for changes in rural ecological behavior. However, understanding the influencing factors of rural environmental behavior in the context of information technology remains an important research topic. OBJECTIVES: This study aims to reveal the influencing factors of rural environmental behavior in the context of information technology to help governments and policymakers develop effective environmental protection strategies. Specifically, the researchers will focus on the extent to which factors such as education level, ecological awareness, economic status, and social participation influence the environmental behavior of rural residents. METHODS: A questionnaire survey was used in this study, and residents of a particular rural area were selected as the research subjects. A questionnaire containing questions on education level, environmental awareness, economic status, social participation, and environmental behavior was designed, and a large amount of data was collected through random sampling. Statistical analysis methods, such as regression and correlation analyses, were used to process and interpret the data. RESULTS: The study's results showed that the education level significantly affected the environmental behavior of rural residents. Residents with higher levels of education were more inclined to take positive ecological protection actions such as waste separation and energy conservation. In addition, environmental awareness was also found to be closely related to environmental behavior, with residents with higher ecological awareness being more concerned about environmental protection and taking action accordingly. Economic status and social participation affected rural residents' environmental behavior to a certain extent but to a lesser extent than education level and ecological awareness. CONCLUSION: Rural environmental behavior in the context of informatization is affected by a combination of factors. To promote rural ecological protection, the government should strengthen investment in education and improve rural residents' education level and environmental awareness. In addition, social organizations and public participation should also be supported to encourage rural residents to actively participate in environmental protection actions. These measures will help to promote a change in ecological behavior in rural areas and achieve the goal of sustainable development.

INTRODUCTION: The ongoing progress in China's rural revitalization and precision poverty alleviation has led to the gradual implementation of environmental improvement initiatives for rural residents. As a result, rural residents' environmental behavior is now being influenced by informatization interventions. With the deepening of these interventions, various environmental behaviors have emerged. Therefore, it is crucial to study the impact of informatization interventions on rural residents' ecological behavior, focusing specifically on garbage classification and water quality enhancement. OBJECTIVES: To improve the level of China's rural habitat improvement, to improve the mechanism of informatization intervention in the environmental behavior of rural residents; to solve the problem of garbage classification and water quality improvement in the environment of rural residents under the background of informatization intervention, and to improve the level of modernization of China's agriculture and rural areas. METHODS: First, using the theory of informatization intervention to establish a model of informatization intervention in the environmental behavior of rural residents; secondly, using the questionnaire method to investigate and analyze the ecological behavior of rural residents under the background of informatization intervention in the case townships; finally, using the model to analyze the results of the survey and establish the relevant principles of environmental improvement under the background of informatization intervention. RESULTS: Under the background of informatization intervention, there is a significant improvement in the environmental behavior of rural residents, and the efficiency of garbage classification is significantly improved compared with the traditional model; the application of informatization intervention has dramatically improved the efficiency of environmental remediation in the case townships, and the informatization intervention can also play a significant role in the improvement of water quality. CONCLUSION: In the continuous process of rural revitalization and precise poverty alleviation work, to strengthen the informatization intervention of rural residents' environment and comprehensively improve the quality level of rural habitat environment, it is crucial to carry out from various aspects and construct informatization.

Abstract Background Radiotherapy is an important treatment for lung cancer, mainly by triggering DNA double-strand breaks to induce cell death. Blocking DNA damage repair can increase the radiosensitivity of tumor cells. Recent studies have identified long noncoding RNAs as key regulators in DNA damage repair. The lncRNA ANRIL was previously shown to be involved in homologous recombination (HR) repair, but its specific mechanism has not been fully elucidated. Methods The downstream interacting miRNAs of ANRIL were predicted according to miRanda software. Fluorescence quantitative PCR was used to detect the expression levels of ANRIL and candidate miRNAs. Clone formation experiment and cell viability assays detect cell viability after ionizing radiation. Apoptosis assay was used to detect the apoptosis of cells after 8 h of ionizing radiation. Western blot analysis and immunofluorescence assays verified the protein expression levels of the downstream target molecule PARP1 of miR-7-5p and key molecules in the HR pathway. Fluorescent reporter gene experiments were used to verify the interaction between ANRIL and miR-7-5p and between miR-7-5p and PARP1. Results Bioinformatics analysis and qPCR validation suggested that miR-7-5p might be a downstream molecule of ANRIL. The expression of miR-7-5p was up-regulated after knockdown of ANRIL, and the expression of miR-7-5p was down-regulated after overexpression of ANRIL. Meanwhile, there was a negative correlation between ANRIL and miR-7-5p expression changes before and after ionizing radiation. The luciferase reporter gene assay confirmed the existence of ANRIL binding site with miR-7-5p, and found that transfection of miR-7-5p inhibitor can reduce the radiation sensitivity of ANRIL-KD cells. A downstream target molecule of miR-7-5p related to HR repair, PARP1, was screened through website prediction. Subsequently, it was confirmed by Western blot and luciferase reporter assays that miR-7-5p could down-regulate the expression of PARP1, and there was a miR-7-5p binding site on the 3'UTR of PARP1 mRNA. This suggests that ANRIL may act as a competitive endogenous RNA to bind miR-7-5p and upregulate the expression of PARP1. Western blot and immunofluorescence staining were used to detect the expression changes of HR repair factors in ANRIL-KD cells after ionizing radiation, and it was found that knockdown of ANRIL can inhibit the expression of PARP1, BRCA1 and Rad51, hinder radiation-induced HR repair, and eventually result in resensitizing ANRIL-KD cells to ionizing radiation. Conclusions Our findings provide evidence that ANRIL targets the miR-7-5p/PARP1 axis to exert its regulatory effect on HR repair, suggesting that altering ANRIL expression may be a promising strategy to overcome radiation resistance.

Abstract Objective To retrospectively analyze CT and MR imaging features of the brain in patients with hydrogen sulfide poisoning based on clinical symptom grading and to investigate their correlations with clinical symptoms and patients’ prognosis. Methods A retrospective analysis was performed of CT and MR imaging data of the brain in 40 patients with hydrogen sulfide poisoning in our hospital. There were four main imaging manifestations. Patients were clinically graded according to the central nervous system symptom scores of the Poisoning Severity Score (PSS) and staged according to the gas inhalation time segment. Based on clinical symptom grading, the frequencies and proportions of four imaging signs that occurred in each group were counted, their development trends were analyzed, and the correlations of imaging features with clinical grading and prognosis were calculated. Results Forty patients were divided into minor, moderate and severe clinical grades and classified into four stages. In patients with minor and moderate clinical grading, only one patient suffered from generalized brain edema at stage 1, with a good prognosis. Patients with severe clinical grade showed the highest probability of presenting with the four imaging signs. The imaging signs were correlated with the severe clinical grade and a poor prognosis (P = 0.000, R = 0.828; P = 0.000, R = 0.858). Conclusion In patients with the severe clinical grade, generalized brain edema and symmetrical hypodensity/abnormal signals in the bilateral basal ganglia and around the lateral ventricles were the main findings and were shown to persist. The presence of imaging signs can assist in the clinically effective evaluation of clinical symptom grade.

To determine whether sarcoplasmic proteins affected water migration in myofibrils during air-drying, with protein denaturation as an indicator of sarcoplasmic protein changes, the extent of sarcoplasmic protein changes in lamb during air-drying was first studied. The results showed that sarcoplasmic protein’s thermal stability decreased and secondary structure changed, indicating sarcoplasmic protein denatured in lamb during air-drying (35 °C, 60% RH, 3 m/s wind speed). Subsequently, the effect of sarcoplasmic protein solutions, dried at different times and rates, on myofibril protein–water interaction was studied in vitro. Two sets of sarcoplasmic protein solutions were dried for 0, 3, 6, and 9 h in a drying oven, resulting in different degrees of change. These two sets with higher or lower drying rates were achieved by controlling the contact area between sarcoplasmic protein solution and air. These dried sarcoplasmic protein solutions were then mixed with extracted myofibril and incubated for 2 h. The results showed a significant increase in T21 relaxation time of the incubation system when sarcoplasmic protein solution was dried at 35 °C for 3 h. This indicated that myofibrillar protein–water interaction was weakened, facilitating water migration from the inside to the outside of myofibrils. The denaturation degree of sarcoplasmic proteins was slowed by a higher drying rate, thereby alleviating the increase in the amount of immobile water within myofibrils when dried for 6 h. In conclusion, the properties of sarcoplasmic proteins were influenced by both drying rate and time, thereby influencing the water migration within myofibrils during air-drying.

Summary: Background: Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT 04288102). Methods: A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs). Findings: Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04–0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00–20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups. Interpretation: Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period. Funding: The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900, 2022YFC2304401), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRC-ID202105,413FZT6).

Abstract Background Severe ionizing radiation (IR)-induced intestinal injury associates with high mortality, which is a worldwide problem requiring urgent attention. In recent years, studies have found that the PHD-HIF signaling pathway may play key roles in IR-induced intestinal injury, and we found that FG-4592, the PHD inhibitor, has significant radioprotective effects on IR-induced intestinal injury. Methods In the presence or absence of FG-4592 treatment, the survival time, pathology, cell viability, cell apoptosis, and organoids of mice after irradiation were compared, and the mechanism was verified after transcriptome sequencing. The data were analyzed using SPSS ver. 19 software. Results Our results show that FG-4592 had significant radioprotective effects on the intestine. FG-4592 improved the survival of irradiated mice, inhibited the radiation damage of intestinal tissue, promoted the regeneration of intestinal crypts after IR and reduced the apoptosis of intestinal crypt cells. Through organoid experiments, it is found that FG-4592 promoted the proliferation and differentiation of intestinal stem cells (ISCs). Moreover, the results of RNA sequencing and Western blot showed that FG-4592 significantly upregulated the TLR4 signaling pathway, and FG-4592 had no radioprotection on TLR4 KO mice, suggesting that FG-4592 may play protective role against IR by targeting TLR4. Conclusion Our work proves that FG-4592 may promote the proliferation and regeneration of ISCs through the targeted regulation of the TLR4 signaling pathway and ultimately play radioprotective roles in IR-induced injury. These results enrich the molecular mechanism of FG-4592 in protecting cells from IR-induced injury and provide new methods for the radioprotection of intestine.

Abstract The quantum Cramér–Rao bound sets a fundamental limit on the accuracy of unbiased parameter estimation in quantum systems, relating the uncertainty in determining a parameter to the inverse of the quantum Fisher information. We experimentally demonstrate near saturation of the quantum Cramér–Rao bound in the phase estimation of a solid-state spin system, provided by a nitrogen-vacancy center in diamond. This is achieved by comparing the experimental uncertainty in phase estimation with an independent measurement of the related quantum Fisher information. The latter is independently extracted from coherent dynamical responses of the system under weak parametric modulations, without performing any quantum-state tomography. While optimal parameter estimation has already been observed for quantum devices involving a limited number of degrees of freedom, our method offers a versatile and powerful experimental tool to explore the Cramér–Rao bound and the quantum Fisher information in systems of higher complexity, as relevant for quantum technologies.

Abstract Background This study aimed to compare the characteristics of carotid plaques between patients with transient ischemic attack (TIA) and ischemic stroke using magnetic resonance (MR) imaging. Methods Patients with a recent ischemic stroke or TIA who exhibited atherosclerotic plaques of carotid arteries in the symptomatic sides determined by MR vessel wall imaging were recruited. The plaque morphology and compositions including intraplaque hemorrhage (IPH), lipid-rich necrotic-core (LRNC) and calcification were compared between TIA and stroke patients. Logistic regression was performed to relate the plaque characteristics to the types of ischemic events. Results A total of 270 patients with TIA or ischemic stroke were recruited. Stroke patients had a significantly higher prevalence of diabetes (42.2% vs. 28.2%, p = 0.021), greater mean wall area (35.1 ± 10.1 mm2 vs. 32.0 ± 7.7 mm2, p = 0.004), mean wall thickness (1.3 ± 0.2 mm vs. 1.2 ± 0.2 mm, p = 0.001), maximum normalized wall index (NWI)(63.9% ± 6.0% vs. 62.2% ± 5.9%, p = 0.023) and %volume of LRNC (9.7% ± 8.2% vs. 7.4% ± 7.9%, p = 0.025) in the carotid arteries compared to those with TIA. After adjustment for clinical factors, above characteristics of carotid arteries were significantly associated with the type of ischemic events. After further adjustment for maximum NWI, this association remained statistically significant (OR, 1.41; CI, 1.01–1.96; p = 0.041). Conclusions Ischemic stroke patients had larger plaque burden and greater proportion of LRNC in carotid plaques compared to those with TIA. This study suggests that ischemic stroke patients had more vulnerable plaques compared to those with TIA.

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

Background and purpose3D pseudo-continuous arterial spin labeling (3D pCASL) is commonly used to measure arterial cerebral blood flow (CBF). The aim of this study was to assess the clinical feasibility and accuracy of 3D pCASL in comparison with dynamic susceptibility contrast (DSC) perfusion imaging in moyamoya disease (MMD).Materials and methodsA total of 174 MMD patients underwent 3D pCASL and DSC-MRI for evaluating cerebral blood perfusion. 3D-pCASL with two single post-labeling delay (PLD) times (1,500 and 2,500 ms) was used to measure CBF. The values of DSC-CBF and ASL-CBF were calculated for major arterial territories including the anterior, middle, and posterior cerebral arteries as well as the areas based on the Alberta Stroke Program Early CT Score (ASPECTS) template. The correlation between DSC-CBF and ASL-CBF was analyzed. The consistency and accuracy between the two methods in assessing the cerebral ischemic state before and after surgery were analyzed.ResultsThe correlation between ASL (2,500 ms) and DSC-MRI was slightly better than the correlation between ASL (1,500 ms) and DSC-MRI in major vascular territories before revascularization. Significant correlations were observed between ASL (2,500 ms) and DSC-MRI and between ASL (1,500 ms) and DSC-MRI in major vascular territories after revascularization. For 44 surgically treated patients, the scores of ASPECTS for CBF on the operated side were significantly different before and after revascularization (p < 0.05) and showed good consistency on all the examination methods. A comparison of the scores of ASPECTS of the three parameters before and after revascularization showed that there was no statistical difference between them (p > 0.05).ConclusionCompared to DSC-MRI, 3D pCASL can assess the cerebral blood perfusion in MMD before and after revascularization effectively. 3D pCASL showed the feasibility and clinical utility value in patients with MMD.

PurposeIn clinical work, accurately measuring the volume and the size of breast cancer is significant to develop a treatment plan. However, it is time-consuming, and inter- and intra-observer variations among radiologists exist. The purpose of this study was to assess the performance of a Res-UNet convolutional neural network based on automatic segmentation for size and volumetric measurement of mass enhancement breast cancer on magnetic resonance imaging (MRI).Materials and methodsA total of 1,000 female breast cancer patients who underwent preoperative 1.5-T dynamic contrast-enhanced MRI prior to treatment were selected from January 2015 to October 2021 and randomly divided into a training cohort (n = 800) and a testing cohort (n = 200). Compared with the masks named ground truth delineated manually by radiologists, the model performance on segmentation was evaluated with dice similarity coefficient (DSC) and intraclass correlation coefficient (ICC). The performance of tumor (T) stage classification was evaluated with accuracy, sensitivity, and specificity.ResultsIn the test cohort, the DSC of automatic segmentation reached 0.89. Excellent concordance (ICC > 0.95) of the maximal and minimal diameter and good concordance (ICC > 0.80) of volumetric measurement were shown between the model and the radiologists. The trained model took approximately 10–15 s to provide automatic segmentation and classified the T stage with an overall accuracy of 0.93, sensitivity of 0.94, 0.94, and 0.75, and specificity of 0.95, 0.92, and 0.99, respectively, in T1, T2, and T3.ConclusionsOur model demonstrated good performance and reliability for automatic segmentation for size and volumetric measurement of breast cancer, which can be time-saving and effective in clinical decision-making.

Short-term taxi demand forecasting is of great importance to incentivize vacant cars moving from over-supply regions to over-demand regions, which can minimize the wait time for passengers and drivers. With the consideration of spatiotemporal dependences, this study proposes a multi-task deep learning (MTDL) model to predict short-term taxi demand in multi-zone level. The nonlinear Granger causality test is applied to explore the causality relationships among various traffic zones, and long short-term memory (LSTM) is used as the core neural unit to construct the framework of the multi-task deep learning model. In addition, several hyperparameter optimization methods (e.g., grid search, random search, Bayesian optimization, hyperopt) are used to tune the model. Using the taxi trip data in New York City for validation, the multi-task deep learning model considering spatiotemporal dependences (MTDL∗) is compared with the single-task deep learning model (STDL), the full-connected multi-task deep learning model (MTDL#) and other benchmark algorithms (such as LSTM, support vector machine (SVM) and k-nearest neighbors (k-NN)). The experiment results show that the proposed MTDL model is promising to predict short-term taxi demand in multi-zone level, the nonlinear Granger causality analysis is able to capture the spatiotemporal correlations among various traffic zones, and the Bayesian optimization is superior to the other three methods, which verified the feasibility and adaptability of the proposed method.

Summary: Background: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. Methods: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). Findings: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of −10.8% (95% CI: −20.7%, −1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. Interpretation: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. Funding: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

As a special territory type, the farming–pastoral ecotone is facing challenges surrounding path creation and high-quality and sustainable development. Counties are not only an important spatial unit to promote high-quality development, but also an important part of the modernization of the national governance system. County-level development is the critical driving force of sustainable development and the breakthrough of governance modernization in the farming-pastoral ecotone. First, this study systematically reviews the progress of the farming–pastoral ecotone and high-quality development. Then, this study adopts the “Driving Forces-Pressure-State-Impact-Responses” (DPSIR) model and entropy method to construct an analysis framework. Third, taking Kulun county as a typical case, this study diagnoses the state of high-quality county-level development in the farming–pastoral ecotone. Finally, a governance mechanism of “idea-space-industry-people’s livelihood-governance” has been proposed. This study provides theoretical guidance for the high-quality development of the farming–pastoral ecotone and enriches the body of knowledge regarding high-quality development.

Lung cancer: Suppressing fibrosis during radiotherapy The risk of scarred tissues and respiratory distress during radiation treatment of lung cancer could be reduced by targeting an enzyme that alters healthy cells. Lung cancer radiotherapy often causes pulmonary fibrosis, excessive growth of fibrous tissues in the lungs, involving the transition of normal epithelial cells into an invasive form of multipotent stem cells. The development of pulmonary fibrosis limits the clinical application of radiotherapy. Hongjin Qu and co-workers at the Second Military University in Shanghai, China, previously demonstrated that the TANK-binding kinase 1 (TBK1) enzyme regulates this transition. Now, the team have shown that levels of TBK1 itself increased during radiation treatment, together with two proteins that would normally suppress alterations in healthy cells. Inhibiting TBK1, both in cell cultures and mouse models, reversed the cell transitions and prevented pulmonary fibrosis.

Ionizing radiation is one of the common environmental carcinogens. miRNAs play critical roles in the processes of tumor occurrence, development, metastasis. However, the relationship between radiation-induced carcinogenesis and miRNA rarely reported. This study is aimed to investigate the effect of miRNAs on radiation-induced carcinogenesis. In this study we established the radiation-induced thymic lymphoma mice model. By using miRNA array of RTL tissue and predicting for miRNAs target genes, a miRNA-mRNA crosstalk network was established. Based on this network, we identified a critical miRNA, miR-486, which was the most down-regulated in the radiation-induced carcinogenesis. Then the function of miR-486 was confirmed by using knockout mice and cellular experiments. As a result, miR-486 could inhibit proliferation of mouse lymphoma cells by targeting IGF2BP3 mRNA. The adenovirus over-expression miR-486 vector reduced tumorigenesis in vivo. MiR-486 knockout mice have a strong tendency of radiation-induced carcinogenesis. In conclusion, miR-486 inhibits the proliferation of lymphoma cells and tumorigenesis induced by radiation through targeting IGF2BP3.

Objective Patients receiving carbon-ion radiation therapy and astronauts exploring outer space are inevitably exposed to heavy ion radiation. The aim of this study was to develop radioprotectors to minimize the injuries induced by carbon ion radiation. Methods Heat-killed Salmonella Typhimurium (HKST) was administered to mice by gavage prior to irradiation with a 12 C 6+ heavy ion accelerator. Hematoxylin and eosin staining and immunofluorescence TdT-mediated dUTP Nick-End Labeling staining were used to assess the radioprotective effect of HKST on organ damage and levels of apoptosis, respectively, in mice. To investigate the mechanism underlying the radioprotective effect of HKST, levels of the pro-apoptotic proteins BAX and caspase 3 as well as interferon-regulatory factor (IRF) 3/7 in the femur, testis and intestine were assessed using immunofluorescence. Results Injuries induced by carbon ion radiation were significantly eased by pretreatment with HKST. Both apoptosis and high expression levels of pro-apoptotic proteins induced by heavy ion radiation were inhibited by HKST pretreatment. The radioprotective effect of HKST was associated with stimulation of Toll-like receptor signaling mediated by enhanced IRF3 and IRF7 signaling. Conclusion HKST was an effective radioprotector alleviating damage to multiple organs caused by heavy ion radiation.

This study aims to investigate the overall impacts of the World Heritage List (WHL) inscription in China from different socioeconomic aspects. Kaiping Diaolou and Villages was chosen as the case study because the long period of preparation for WHL inscription led to residents’ deep understanding of its heritage values. Results are as follows. (1) Cultural cognition, sense of belonging, community cohesion and infrastructure were positively improved by the WHL inscription, whereas damage to the community cultural environment slightly increased. (2) In the economic domain, the WHL inscription had generated positive (increase in tourism development and villagers’ income and employment and solution to the Diaolou property rights problem) and negative impacts (worse tourism development, unequal income and unsolved property rights problems). (3) The WHL inscription improved the ecological environment and people’s attention to environmental protection. Although it also caused environmental damage due to an increase in tourists. (4) The positive impacts on the political domain were reflected by government leadership, community participation and plan and legislation, whereas the negative impacts included limited community participation and insufficient planning. Innovations of this study include constructing a theoretical framework to evaluate the impacts of WHL inscription, analysing the present factors of WHL inscription’s impacts and providing development suggestions. First published online 22 October 2019

Accurate prediction and reliable significant factor analysis of incident clearance time are two main objects of traffic incident management (TIM) system, as it could help to relieve traffic congestion caused by traffic incidents. This study applies the extreme gradient boosting machine algorithm (XGBoost) to predict incident clearance time on freeway and analyze the significant factors of clearance time. The XGBoost integrates the superiority of statistical and machine learning methods, which can flexibly deal with the nonlinear data in high-dimensional space and quantify the relative importance of the explanatory variables. The data collected from the Washington Incident Tracking System in 2011 are used in this research. To investigate the potential philosophy hidden in data, K-means is chosen to cluster the data into two clusters. The XGBoost is built for each cluster. Bayesian optimization is used to optimize the parameters of XGBoost, and the MAPE is considered as the predictive indicator to evaluate the prediction performance. A comparative study confirms that the XGBoost outperforms other models. In addition, response time, AADT (annual average daily traffic), incident type, and lane closure type are identified as the significant explanatory variables for clearance time.

Background/Aims: Ovarian cancer (OC) is the fifth leading cause of cancer-related death in women, and it is difficult to diagnose at an early stage. The purpose of this study was to explore the prognostic biological markers of OC. Methods: Univariate Cox regression analysis was used to identify genes related to OC prognosis from the Cancer Genome Atlas(TCGA) database. Immunohistochemistry was used to analyse the level of SPINK13 in OC and normal tissues. Cell proliferation, apoptosis and invasion were performed using MTT assay, flow cytometric analysis and Transwell assay, respectively. Results: We identified the Kazal-type serine protease inhibitor-13 (SPINK13) gene related to OC prognosis from the Cancer Genome Atlas (TCGA) database by univariate Cox regression analysis. Overexpression of SPINK13 was associated with higher overall survival rate in OC patients. Immunohistochemistry showed that the level of SPINK13 protein was significantly lower in OC tissues than in normal tissues (P < 0.05).In vitro experiments showed that the overexpression of SPINK13 inhibited cellular proliferation and promoted apoptosis. Moreover, SPINK13 inhibited cell migration and epithelial to mesenchymal transition (EMT). SPINK13 was found to inhibit the expression of urokinase-type plasminogen activator (uPA), while recombinant uPA protein could reverse the inhibitory effect of SPINK13 on OC metastasis. Conclusion: These results indicate that SPINK13 functions as a tumour suppressor. The role of SPINK13 in cellular proliferation, apoptosis and migration is uPA dependent, and SPINK13 may be used as a potential biomarker for diagnosis and targeted therapy in OC.

The quantum Fisher information (QFI) represents a fundamental concept in quantum physics. It quantifies the metrological potential of quantum states in quantum parameter estimation measurements, and is intrinsically related to quantum geometry and multipartite entanglement of many-body systems. Using a nitrogen-vacancy center spin in diamond, we experimentally demonstrate a randomized-measurement method to extract the QFI of the qubit, for both pure and mixed states. We then apply this scheme to a 4-qubit state, using a superconducting quantum computer, and show that it provides access to the sub-QFI, which sets a lower bound on the QFI for general mixed states. We numerically study the scaling of statistical error, considering N-qubit states, to illustrate the advantage of our randomized-measurement approach in estimating the QFI and multipartite entanglement. Our results highlight the general applicability of our method to different quantum platforms, including solid-state spin systems, superconducting quantum computers, and trapped ions.

Background/Aims: This study investigated the radioprotective properties of three classes of CpG-oligodeoxynucleotides (CpG-ODNs) and the underlying mechanisms. Methods: Mice irradiated at different doses(7Gy or 9Gy) were treated with or without ODNs(50μg via intraperitoneal injection). Assays were performed to determine survival rate and the number of white blood cell in peripheral blood. The levels of granulocyte-colony stimulating factor(G-CSF), interleukin 6(IL-6) and interferon-α (IFN-α) were measured using enzyme-linked immunosorbent assay (ELISA). Results: Survival rate of mice irradiated in 7Gy was increased from 50% to about 100% with ODNs pretreatment. ODNs administration increased the number of WBCs of irradiated mice. G-CSF, IL-6 and IFN-α levels were up-regulated with ODNs treatment. Conclusion: All three classes of ODNs protected mice from irradiation-induced injuries. B-class ODNs exhibited the most potent radioprotective property via the up-regulation of G-CSF and IL-6.

Background/Aims: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI. Methods: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O2) or hypoxic conditions (2.5% O2). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included H&E staining, Masson staining and α-SMA staining; meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting. Results: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance. Conclusion: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

Background/Aims: The hematopoietic system is vulnerable to ionizing radiation and is often severely damaged by radiation. Molecules affecting radioresistance include Toll-like receptor 2. We investigated whether Zymosan-A, a novel TLR2 agonist, can protect the hematopoietic system from radiation-induced damage after total body irradiation. Methods: Mice were exposed to total body radiation after treatment with Zymosan-A or normal saline, and their survival was recorded. Tissue damage was evaluated by hematoxylin–eosin staining. The number of nucleated cells in bone marrow was determined by flow cytometry. Cell viability and apoptosis assay were determined by CCK-8 assay and flow cytometry assay. Enzyme-linked immunosorbent assay was used to detect the level of cytokines. Results: Zymosan-A protected mice from radiation-induced death and prevented radiation-induced hematopoietic system damage. Zymosan-A also promoted cell viability and inhibited cell apoptosis caused by radiation, induced radioprotective effects via TLR2, upregulated IL-6, IL-11, IL-12, and TNF-α in vivo. Conclusion: Zymosan-A can provide protection against radiation-induced hematopoietic system damage by targeting the TLR2 signaling pathway. Thus, Zymosan-A can be potentially effective radioprotectant.

Background/Aims: Polymyxin B (PMB) is a cyclic cationic polypeptide antibiotic widely used to counteract the effects of endotoxin contamination, both in vitro and in vivo. Lipopolysaccharide (LPS) is an endotoxin that acts as a radiation protection factor. In this study, we focus on the role of PMB in LPS-induced and radiation-induced mortality in mice. Methods: Mice received total-body radiation or were pretreated by LPS or PMB, and the survival of mice was recorded. Elisa were used to detect the cytokines levels. Results: PMB decreased LPS-induced, but increased radiation-induced mortality in mice. Moreover, PMB could block the LPS-induced radioprotective effect. The ELISA and gene knock-out experiments indicated that PMB reduces TNF-α level to block LPS-induced mortality in mice, and inhibits IL-6, G-CSF and IL-10 to increase radiation-induced mortality via the TLR4-Myd88-IL-6 pathway. Conclusions: Our study revealed a role of PMB in LPS-induced endotoxemia and radiation exposure. We infer that the TLR4-Myd88-IL-6 pathway may play a crucial role in the process.

Endotoxin damage is an acute, multi-organ disease, the most typical symptoms of which are liver injury and inflammatory cytokine storm. Endotoxin tolerance is described as the pretreatment of lipopolysaccharides (LPS) before the toxin invasion, which is consistent with the adaptive response induced by low-dose radiation (LDR). In this study, we verified that LDR could resist the endotoxin damage by suppressing the increase of inflammatory cytokines, including interleukin 6, tumor necrosis factor, and NO, to improve the survival and relieve the inflammatory cell infiltration, in which low dose of LPS performed consistently with LDR.

The small intestine is one of the most sensitive organs to irradiation injury, and the development of high effective radioprotectants especially with low toxicity for intestinal radiation sickness is urgently needed. Monophosphoryl lipid A (MPLA) was found to be radioprotective in our previous study, while its effect against the intestinal radiation injury remained unknown. In the present study, we firstly determined the intestinal apoptosis after irradiation injury according to the TUNEL assay. Subsequently, we adopted the immunofluorescence technique to assess the expression levels of different biomarkers including Ki67, γ-H2AX, and defensin 1 in vivo. Additionally, the inflammatory cytokines were detected by RT-PCR. Our data indicated that MPLA could protect the intestine from ionizing radiation (IR) damage through activating TLR4 signal pathway and regulating the inflammatory cytokines. This research shed new light on the protective effect of the novel TLR4 agonist MPLA against intestine detriment induced by IR.