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BackgroundFufang Yinhua Jiedu (FFYH) granules are recommended for treating coronavirus pneumonia (COVID-19) in China. However, its anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity and clinical efficacy against COVID-19 remain to be confirmed.AimsOur study aimed to investigate the anti-SARS-CoV-2 effect and potential mechanism of FFYH.Materials and MethodsThe activity of FFYH against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated via cell pathogenic effects, immunoblotting, immunofluorescence staining, and qRT-PCR. The potential mechanism of FFYH against SARS-CoV-2 was investigated by immunoblotting. One head-to-head randomized controlled trial was designed to evaluate the clinical efficacy of FFYH in mild COVID-19. Two hundred patients were randomly recruited to receive either FFYH or LHQW (Lianhua Qingwen) granules.ResultsThe in vitro results indicated that FFYH effectively inhibited SARS-CoV-2 replication by suppressing CPE and decreasing viral RNA and protein expression. A time-of-drug-addition assay confirmed that FFYH mainly targeted the binding and replication stages of the SARS-CoV-2 life cycle. Mechanistic studies revealed that blocking SARS-CoV-2-triggered autophagy may be the primary mechanism by which FFYH protects against SARS-CoV-2 infection by regulating the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Clinical results confirmed that FFYH effectively shortened the recovery time of clinical symptoms and viral nucleic acid negativity, improved abnormal hematology parameters, and controlled excessive cytokine responses in mild COVID-19 patients. Subgroup analysis revealed that FFYH improved the recovery time of clinical symptoms, improved hematological parameters, and controlled excessive cytokine storms to a greater extent in the mild COVID-19 male subgroup, abnormal hematology subgroup, and 32–42-year-old subgroup than in the corresponding LHQW subgroup (P < 0.05). No patients progressed to severe or critical cases.ConclusionOur results indicate that FFYH not only has good anti-viral activity against SARS-CoV-2 but also has significant efficacy against COVID-19, indicating that FFYH may be a novel complementary option for treating COVID-19.

Objective: To formulate an efficacious radioprotective combination of Chinese medicines with minimal toxicity. Methods: Aqueous and alcoholic extracts from 38 traditional Chinese herbs were prepared. To produce drug-containing sera, rats received six doses of each extract via oral gavage at 12-h intervals. Subsequently, human lung epithelial BEAS-2B cells were cultured in these drug-containing sera. The cell viability was assessed after different doses of irradiation to identify the radioprotective effects of Chinese herbal extracts. The efficacy of a selected Chinese herbal extract combination was further confirmed through cell viability analysis via in vitro colony formation and survival rate assessments in C57BL/6 mice post-irradiation. Results: Extracts from Angelicae Sinensis Radix (ASR; two extracts), Citri Reticulatae Pericarpium (CRP), Platycladi Cacumen (PC), Schisandrae chinensis Fructus (SF), Scutellariae Radix (SR), and Glycyrrhizae Radix et Rhizome (GRR) demonstrated radioprotective effects. The combination of the seven Chinese herbal extracts notably increased the survival and viability of the BEAS-2B cells exposed to varying doses of X-rays. Moreover, the group of mice receiving Chinese medicine combination and irradiation exhibited prolonged survival after exposure to 6.5 ​Gy X-rays with a median survival of （14 ​± ​2）d compared to （11 ​± ​2）d in the irradiated group without the herbal treatment. Additionally, the Chinese medicine combination group displayed a significantly higher 28 ​d survival rate (30%) compared to the irradiation-only group (16.6%, P ​

Abstract The immunological implications of cuproptosis, a form of cell death highly sensitive to oxygen presence, remain largely unexplored in the context of tumor immunotherapy. Herein, we initially investigate the positive correlation between cuproptosis and tumor immunotherapy through bioinformatics analysis. Subsequently, an oxygen generator loaded with copper ions (Cu/APH‐M) has been constructed, which serves as an effective carrier of copper ions and crucially enhances the oxygenation of the tumor microenvironment. Importantly, Cu/APH‐M‐mediated dual strengthening of cuproptosis and radiotherapy could not only trigger a powerful antitumor immunity related to immunogenic cell death by RNA‐sequencing analysis, but also effectively inhibit the growth of both distal and in situ low rectal tumors after combined immunotherapy, creating a robust immune memory effect. Our work reveals the beneficial effects of enhanced cuproptosis in radio‐immunotherapy and elucidates its underlying mechanisms, which provides a novel approach for the synergistic integration of cuproptosis with immunotherapy and radiotherapy, broadening the scope of cuproptosis‐mediated tumor therapy.

The EU conducted the pre-conceptual design (PCD) phase of the demonstration reactor (DEMO) during 2014–2020 under the framework of the EUROfusion consortium. The current strategy of DEMO design is to bridge the breeding blanket (BB) technology gaps between ITER and a commercial fusion power plant (FPP) by playing the role of a “Component Test Facility” for the BB. Within this strategy, a so-called driver blanket, with nearly full in-vessel surface coverage, will aim at achieving high-level stakeholder requirements of tritium self-sufficiency and power extraction for net electricity production with rather conventional technology and/or operational parameters, while an advanced blanket (or several of them) will aim at demonstrating, with limited coverage, features that are deemed necessary for a commercial FPP. Currently, two driver blanket candidates are being investigated for the EU DEMO, namely the water-cooled lithium lead and the helium-cooled pebble bed breeding blanket concepts. The PCD phase has been characterized not only by the detailed design of the BB systems themselves, but also by their holistic integration in DEMO, prioritizing near-term solutions, in accordance with the idea of a driver blanket. This paper summarizes the status for both BB driver blanket candidates at the end of the PCD phase, including their corresponding tritium extraction and removal (TER) systems, underlining the main achievements and lessons learned, exposing outstanding key system design and R&D challenges and presenting identified opportunities to address those risks during the conceptual design (CD) phase that started in 2021.

Abstract Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.

In the human genome, 98% of genes can be transcribed into non-coding RNAs (ncRNAs), among which lncRNAs and their encoded peptides play important roles in regulating various aspects of cellular processes and may serve as crucial factors in modulating the biological effects induced by ionizing radiation and microgravity. Unfortunately, there are few reports in space radiation biology on lncRNA-encoded peptides below 10kD due to limitations in detection techniques. To fill this gap, we integrated a variety of methods based on genomics and peptidomics, and discovered 22 lncRNA-encoded small peptides that are sensitive to space radiation and microgravity, which have never been reported before. We concurrently validated the transmembrane helix, subcellular localization, and biological function of these small peptides using bioinformatics and molecular biology techniques. More importantly, we found that these small peptides function independently of the lncRNAs that encode them. Our findings have uncovered a previously unknown human proteome encoded by 'non-coding' genes in response to space conditions and elucidated their involvement in biological processes, providing valuable strategies for individual protection mechanisms for astronauts who carry out deep space exploration missions in space radiation environments.

Abstract Background Aberrant RNA editing of adenosine-to-inosine (A-to-I) has been linked to multiple human cancers, but its role in intrahepatic cholangiocarcinoma (iCCA) remains unknown. We conducted an exome-wide investigation to search for dysregulated RNA editing that drive iCCA pathogenesis. Methods An integrative whole-exome and transcriptome sequencing analysis was performed to elucidate the RNA editing landscape in iCCAs. Putative RNA editing sites were validated by Sanger sequencing. In vitro and in vivo experiments were used to assess the effects of an exemplary target gene Kip1 ubiquitination-promoting complex 1 (KPC1) and its editing on iCCA cells growth and metastasis. Crosstalk between KPC1 RNA editing and NF-κB signaling was analyzed by molecular methods. Results Through integrative omics analyses, we revealed an adenosine deaminases acting on RNA 1A (ADAR1)-mediated over-editing pattern in iCCAs. ADAR1 is frequently amplified and overexpressed in iCCAs and plays oncogenic roles. Notably, we identified a novel ADAR1-mediated A-to-I editing of KPC1 transcript, which results in substitution of methionine with valine at residue 8 (p.M8V). KPC1 p.M8V editing confers loss-of-function phenotypes through blunting the tumor-suppressive role of wild-type KPC1. Mechanistically, KPC1 p.M8V weakens the affinity of KPC1 to its substrate NF-κB1 p105, thereby reducing the ubiquitinating and proteasomal processing of p105 to p50, which in turn enhances the activity of oncogenic NF-κB signaling. Conclusions Our findings established that amplification-driven ADAR1 overexpression results in overediting of KPC1 p.M8V in iCCAs, leading to progression via activation of the NF-κB signaling pathway, and suggested ADAR1-KPC1-NF-κB axis as a potential therapeutic target for iCCA.

The fusion program in the Karlsruhe Institute of Technology (KIT) leads the R&D of the DEMO helium-cooled pebble bed (HCPB) breeding blanket within the work package breeding blanket (WPBB) of the Eurofusion Consortium in the European Union (EU). A new design of the HCPB breeder zone, with a layout inspired by a nuclear reactor fuel rod arrangement, was developed recently and called the fuel-breeder pin concept. In addition, a mock-up (MU) of this fuel-breeder pin was designed and manufactured at KIT in order to test and validate its thermal–hydraulic performance. This paper reports on the results of the first experimental campaign dedicated to the fuel-breeder pin MU testing that was performed in the Helium Loop Karlsruhe (HELOKA) facility. The paper presents: (i) the integration of the fuel-breeder pin MU into the HELOKA loop including considerations of the experimental set-up, (ii) an overview of the plan for the experimental campaigns, and (iii) a discussion of the experimental results with a focus on aspects relevant for the validation of the thermal–hydraulic design of the HCPB breeder zone.

A large number of studies have reported that tumor cells are often out of sync with the surrounding healthy tissue. Exploiting this misalignment may be a way to obtain a substantial gain in the therapeutic window. Specifically, based on reports to date, we will assess whether radiotherapy outcomes differ depending on the administration time. Collectively, 24 studies met the inclusion criteria, out of which 12 at least reported that radiation therapy is less toxic when administered at a particular time, probably because there is less collateral damage to healthy cells. However, discrepancies exist across studies and urge further investigation. Mechanistic studies elucidating the relationship between radiotherapy, circadian rhythms, and cell cycle, combined with either our “digital” or “biological” chronodata, would help oncologists successfully chronotype individual patients and strategize treatment plans accordingly.

Social media fitness influencers are driving the maturation of online fitness, which is especially significant in the current era of globally decreasing levels of physical activity. However, there is a paucity of research on online fitness videos, and the mechanism of influence of fitness videos on exercise intention is not well understood. Therefore, based on the stimulus–organism–response (S-O-R) theoretical framework, this study extends the source credibility theory to the field of fitness and adds an examination of the content quality and electronic word-of-mouth of fitness videos to explore how fitness videos motivate users to participate in physical exercise. Through an online survey, 367 valid samples were collected and validated using a structural equation model. The results showed that the three elements contained in source credibility theory have inconsistent importance in the fitness field, with trustworthiness being the most important, followed by attractiveness, and the influence of expertise is not significant. In summary, the attributes of social media fitness influencers, including trustworthiness and physical attractiveness, as well as the content quality and electronic word-of-mouth of their fitness videos, may lead to viewers’ trust and perception of the usefulness of the videos and, furthermore, lead to exercise intention.

Abstract Long noncoding RNAs (lncRNAs) in eukaryotic transcripts have long been believed to regulate various aspects of cellular processes, including carcinogenesis. Herein, it is found that lncRNA AFAP1‐AS1 encodes a conserved 90‐amino acid peptide located on mitochondria, named lncRNA AFAP1‐AS1 translated mitochondrial‐localized peptide (ATMLP), and it is not the lncRNA but the peptide that promotes the malignancy of nonsmall cell lung cancer (NSCLC). As the tumor progresses, the serum level of ATMLP increases. NSCLC patients with high levels of ATMLP display poorer prognosis. Translation of ATMLP is controlled by m6A methylation at the 1313 adenine locus of AFAP1‐AS1. Mechanistically, ATMLP binds to the 4‐nitrophenylphosphatase domain and non‐neuronal SNAP25‐like protein homolog 1 (NIPSNAP1) and inhibits its transport from the inner to the outer mitochondrial membrane, which antagonizes the NIPSNAP1‐mediated regulation of cell autolysosome formation. The findings uncover a complex regulatory mechanism of NSCLC malignancy orchestrated by a peptide encoded by a lncRNA. A comprehensive judgment of the application prospects of ATMLP as an early diagnostic biomarker for NSCLC is also made.

Abstract Mechanotransduction sensing of tissue architecture and cellular microenvironment is a fundamental regulator of cell fate, including cancer. Meanwhile, long noncoding RNAs (lncRNAs) play multifunctions during cancer development and treatment. However, the link between lncRNAs and cellular mechanotransduction in the context of cancer progression has not yet been elucidated. In this study, using atomic force microscopy (AFM), we find that ionizing radiation reduces tumor stiffness. Ionizing radiation-induced lncRNA CRYBG3 can blunt YAP/TAZ activity through interference with mechanotransduction, resulting in the inhibition of cell proliferation, invasion, and metastasis of lung cancer cells. In vivo, we found that loss of lncRNA CRYBG3 could power the tumor initiation and metastasis ability, but this was abolished by concomitant deplete TAZ. At the molecular level, lncRNA CRYBG3 that in turn dysregulates F-actin organization, activates the LATS1/2 kinase, all in all resulting in YAP/TAZ nuclear exclusion. Our research proposes that lncRNA CRYBG3 is a mediator of radiotherapy through its control of cancer-tissue mechanotransduction and wiring YAP/TAZ activity to control tumor growth and metastasis.

The integration of photothermal therapy (PTT) with gene therapy (GT) in a single nanoscale platform demonstrates great potential in cancer therapy. Porous iron oxide nanoagents (PIONs) are widely used as magnetic nanoagents in the drug delivery field and also serve as a photothermal nanoagent for photothermal therapy. However, the therapeutic efficacy of PIONs-mediated GT has not been studied. The long noncoding RNA (lncRNA) CRYBG3 (LNC CRYBG3), a lncRNA induced by heavy ion irradiation in lung cancer cells, has been reported to directly bind to globular actin (G-actin) and cause degradation of cytoskeleton and blocking of cytokinesis, thus indicating its potential for use in GT by simulating the effect of heavy ion irradiation and functioning as an antitumor drug. In the present study, we investigated the possibility of combining PIONs-mediated PTT and LNC CRYBG3-mediated GT to destroy non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. The combination therapy showed a high cancer cell killing efficacy, and the cure rate was better than that achieved using PTT or GT alone. Moreover, as a type of magnetic nanoagent, PIONs can be used for magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) both in vitro and in vivo. These findings indicate that the new combination therapy has high potential for cancer treatment.

Single-cell transcriptomics offers opportunities to investigate ligand-receptor (LR) interactions between heterogeneous cell populations within tissues. However, most existing tools for the inference of intercellular communication do not allow prioritization of functional LR associations that provoke certain biological responses in the receiver cells. In addition, current tools do not enable the identification of the impact on the downstream cell types of the receiver cells. We present CommPath, an open-source R package and webserver, to analyze and visualize the LR interactions and pathway-mediated intercellular communication chain with single-cell transcriptomic data. CommPath curates a comprehensive signaling pathway database to interpret the consequences of LR associations and therefore infers functional LR interactions. Furthermore, CommPath determines cell-cell communication chain by considering both the upstream and downstream cells of user-defined cell populations. Applying CommPath to human hepatocellular carcinoma dataset shows its ability to decipher complex LR interaction patterns and the associated intercellular communication chain, as well as their changes in disease versus homeostasis.

Introduction Varicocele (VC) is a common clinical disease in andrology. Among a number of ways for VC treatment, surgery is the most common one, but the measurable benefit of surgical repair was slight. A growing exploration of complementary therapies has been conducted in clinical research on acupuncture for VC, but there is no relevant systematic review and meta-analysis to assess the efficacy and safety of acupuncture for VC.Methods and analysis All relevant publications published from database inception through August 2022 will be searched in three English-language databases (Embase, CENTRAL, MEDLINE) and four Chinese-language databases (China National Knowledge Infrastructure, China Science and Technology Journal Database, Chinese Biomedical Literature Database and Wanfang Data). Randomised controlled trials in English and Chinese concerned with acupuncture for patients with VC will be included. The input clinical data will be processed by the Review Manager software (RevMan). The literature will be appraised with the Cochrane Collaboration risk of bias tool. The Grading of Recommendations Assessment, Development and Evaluation system (GRADE system) will be used to evaluate the quality of evidence.Ethics and dissemination This study is a secondary study based on clinical studies so it does not relate to any individual patient information or infringe the rights of participants. Hence no ethical approval is required. The results will be reported in peer-reviewed journals or disseminated at relevant conferences.PROSPERO registration number CRD42022316005.

The carcinogenic risk from space radiation has always been a health risk issue of great concern during space exploration. In recent years, a large number of cellular and animal experiments have demonstrated that space radiation, composed of high-energy protons and heavy ions, has shown obvious carcinogenicity. However, different from radiation on Earth, space radiation has the characteristics of high energy and low dose rate. It is rich in high-atom-number and high-energy particles and, as it is combined with other space environmental factors such as microgravity and a weak magnetic field, the study of its carcinogenic effects and mechanisms of action is difficult, which leads to great uncertainty in its carcinogenic risk assessment. Here, we review the latest progress in understanding the effects and mechanisms of action related to cell transformation and carcinogenesis induced by space radiation in recent years and summarize the prediction models of cancer risk caused by space radiation and the methods to reduce the uncertainty of prediction to provide reference for the research and risk assessment of space radiation.

Background: Cellular senescence plays a complicated and vital role in cancer development because of its divergent effects on tumorigenicity. However, the long non-coding RNAs (lncRNAs) associated with tumor senescence and their prognostic value in hepatocellular carcinoma (HCC) remain unexplored.Methods: The trans-cancer oncogene-induced senescence (OIS) signature was determined by gene set variation analysis (GSVA) in the cancer genome atlas (TCGA) dataset. The OIS-related lncRNAs were identified by correlation analyses. Cox regression analyses were used to screen lncRNAs associated with prognosis, and an optimal predictive model was created by regression analysis of the least absolute shrinkage and selection operator (LASSO). The performance of the model was evaluated by Kaplan-Meier survival analyses, nomograms, stratified survival analyses, and receiver operating characteristic curve (ROC) analyses. Gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) were carried out to explore the functional relevance and immune cell infiltration, respectively.Results: Firstly, we examined the pan-cancer OIS signature, and found several types of cancer with OIS strongly associated with the survival of patients, including HCC. Subsequently, based on the OIS signature, we identified 76 OIS-related lncRNAs with prognostic values in HCC. We then established an optimal prognostic model based on 11 (including NRAV, AC015908.3, MIR100HG, AL365203.2, AC009005.1, SNHG3, LINC01138, AC090192.2, AC008622.2, AL139423.1, and AC026356.1) of these lncRNAs by LASSO-Cox regression analysis. It was then confirmed that the risk score was an independent and potential risk indicator for overall survival (OS) (HR [95% CI] = 4.90 [2.74–8.70], p < 0.001), which outperforms those traditional clinicopathological factors. Furthermore, patients with higher risk scores also showed more advanced levels of a proinflammatory senescence-associated secretory phenotype (SASP), higher infiltration of regulatory T (Treg) cells and lower infiltration of naïve B cells, suggesting the regulatory effects of OIS on immune microenvironment. Additionally, we identified NRAV as a representative OIS-related lncRNA, which is over-expressed in HCC tumors mainly driven by DNA hypomethylation.Conclusion: Based on 11 OIS-related lncRNAs, we established a promising prognostic predictor for HCC patients, and highlighted the potential immune microenvironment-modulatory roles of OIS in HCC, providing a broad molecular perspective of tumor senescence.

Significant design efforts were undertaken during the Pre-Concept Design (PCD) phase of the European DEMO program to optimize the helium cooled pebble bed (HCPB) breeding blanket. A gate review was conducted for the entire European DEMO program at the conclusion of the PCD phase. This article presents a summary of the design evolution and the rationale behind the HCPB breeding blanket concept for the European DEMO. The main performance metrics, including nuclear, thermal hydraulics, thermal mechanical, and tritium permeation behaviors, are reported. These figures demonstrate that the HCPB breeding blanket is a highly effective tritium-breeding and robust driver blanket concept for the European DEMO. In addition, three alternative concepts of interest were explored. Furthermore, this article outlines the upcoming design and R&D activities for the HCPB breeding blanket during the Concept Design phase (2021–2027).

Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell‐based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome‐based pathway analysis of in vitro‐expanded human bone marrow‐derived mesenchymal stem cell (hBM‐MSCs), supplemented with cellular assays focusing on DNA double‐strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (γ‐H2AX + 53BP1 foci) and repair (pBRCA1 + γ‐H2AX foci) of X‐ray‐induced DNA DSBs in hBM‐MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3‐ to fourfold reduction of their mRNA expression by qRT‐PCR. We conclude that the in vitro expansion of hMSCs can lead to aging‐related impairment of the recognition and repair of DNA breaks.

Different from conventional radiotherapy (CONV-RT), FLASH radiotherapy (FLASH-RT) delivers a single high dose at a mean dose rate ≥40 ​Gy/s in milliseconds to achieve similar tumor control to CONV-RT while sparing normal tissues from detrimental injury. It provides an intriguing perspective in improving clinical outcomes for tumor patients as well as a novel way to enhance the differential responses between normal and tumor tissues. However, its mechanisms remain largely unclear. In this paper, we review the currently available publications on FLASH-RT and parse the probable mechanisms of three major aspects including the production of reactive oxygen species, DNA damage response, and immunoreaction. Experiments specifically designed to disclose the intrinsic difference between normal and malignant cells in response to FLASH-RT and CONV-RT are necessary to prove these hypotheses.

The Helium Cooled Pebble Bed (HCPB) breeding blanket is one of the two driver-blanket candidates for the European fusion demonstration power plant (EU DEMO) within the framework of the EUROfusion Consortium. As the EU DEMO program is going, testing of mockups becomes increasingly important. In this article, the engineering design of a first-ever breeder zone mockup of the EU DEMO HCPB breeding blanket is reported. The mockup will be tested in the high-pressure, high temperature, helium facility (HELOKA) at Karlsruhe Institute of Technology. This mockup will act as a test rig to validate heat transfer correlations, CFD software, and thermal hydraulics systems codes. As pressure equipment, the mockup shall conform to the latest European Union Pressure Equipment Directive 2014/68/EU. The design description, rationale and test matrix, and corresponding analyses are discussed and presented.

Innovative Water cooled Lead Ceramic Breeder (WLCB) blanket concepts are being developed at Karlsruhe Institute of Technology (KIT) to explore alternative options for the European demonstration fusion power plant (DEMO). Compared to the Helium Cooled Pebble Bed blanket (HCPB, which is one of the two driver blanket concepts of the European DEMO), Lead/ Lead-alloy is used as neutron multiplier instead of Be/Be-alloy and pressurized subcooled water is used as coolant instead of Helium in the WLCB. The tritium self-sufficiency is the vital function that a Breeding Blanket has to achieve. The absorption of neutrons by water leads to a decrease in the number of neutrons, so the requirement to improve the tritium breeding capacity of the water-cooled blankets is particularly prominent. The Monte Carlo neutron transport code Serpent-2 developed by VTT in Finland has already been benchmarked to be applicable to neutronics calculations in the fusion reactors in a previous study. In this paper, an exploratory TBR study on Water cooled Lead Ceramic Breeder Blanket is presented.

An implantation cyst after orbital wall reconstruction may present as a late complication, which can cause local pain, proptosis, diplopia, and vision impairment. Previous surgical strategies prefer transconjunctival or subtarsal approach for cyst drainage, a similar approach to orbital wall reconstruction. These strategies may have risk of secondary infection. Herein, we propose an endoscopic transnasal surgical approach, through which the removal of implant and cyst drainage can be performed conveniently. The residual, medial single-layer cyst wall is generally strong enough to support the orbital soft tissues without the need for a new implant. We believe this surgical approach can simplify the procedure, reduce the complications, and prevent cyst recurrence.

For electrified transportation (eTransportation) systems, multi-phase motors can provide higher performance and reliability than three-phase ones, but also bring more challenges in their optimal design and control. In this article, a set of high reliable electric drive system based on dual three-phase permanent magnet synchronous motor (DTP PMSM) is developed for auxiliary systems in eTransportation field. A digital collaborative develop process is proposed with the support of multiple software tools. Design, manufacture, and bench testing stages of the DTP PMSM, the two-level six-phase inverter, and the control algorithm are efficiently incorporated. A prototype of the multi-phase electric drive system is fabricated and tested. Comparison of the simulation analysis and experimental results confirms the effectiveness of the collaborative develop progress. Control algorithms based on dual d-q model and vector space decomposition model are both verified and compared via the bench test. Operation mode switching from six-phase mode to three-phase mode is also realized with the prototype system, verifying its capability in fault-tolerant and potential in efficiency optimizing.

Abstract Background Cerium oxide nanoparticles (CeO2 NPs) have potential application for use in biomedical and in various consumer products. However, it is largely unclear whether CeO2 NPs have effects on male reproductive function. Methods In this study, male mice were examined for toxicity, if any, following chronic oral administration of CeO2 NPs for 32 days. In each animal, epididymides were examined for sperm motility and DNA integrity. Bloods were tested for testosterone levels. Testicular tissues were collected to determine the element Ce content, the daily sperm production (DSP), marker enzymes such as ACP, G6PD, γ-GT and SDH, mRNA expression levels of steroidogenesis genes Star, P450scc, P450c17, 3β-Hsd, and 17β-Hsd, as well as steroidogenic factor-1 (SF-1) gene/protein levels. Results The results showed that CeO2 NPs (20 mg/kg and 40 mg/kg) increased the element Ce content in testis, the testis histopathological patterns and sperm DNA damage whereas decreased the testis weight, DSP and sperm motility. There were also remarkable reduction in testosterone levels and marker enzymes activities, down-regulated mRNA expression levels of several steroidogenesis genes such as Star, P450scc, P450c17, 3β-Hsd, and 17β-Hsd, as well as altered gene and protein expressions of SF-1. Conclusion These results reveal the male reproductive toxicity of chronic exposure of CeO2 NPs in mice, hinting that the utilization of CeO2 NPs need to be carefully evaluated about their potential reproductive toxicity on the human health.

The helium-cooled pebble bed (HCPB) breeding blanket (BB) is one of the two driver-blanket candidates for the European DEMO fusion reactor. Recent design activities were focused, among other objectives, on the achievement of an efficient shielding system to adequately protect the vacuum vessel (VV) and toroidal field coils (TFCs). Several shielding options have been studied in terms of architecture (e.g., in-BB shield and ex-BB shield) and materials (e.g., B4C, WC, WB, YHx, and ZrHx). In this study, the B4C material was selected as the most attractive option considering not only shielding performance but also availability, industrialization, experience, and cost factors. Subsequently, we performed a parametric study by implementing different thicknesses of a B4C external shield and reporting information of its effect on shielding performance, structural behavior, swelling and tritium breeding. Furthermore, a detailed structure for the VV was developed considering an internal layered configuration comprising steels/water with different boron contents. Corresponding shielding analyses were conducted regarding influence on neutron attenuation when implementing such a VV structure for both the baseline consolidated design of the HCPB and one of the previously developed and improved BSS configurations. The most critical responses (neutron flux and dpa) were fully established only using 10 cm B4C and an improved VV configuration.

Hadron therapy with protons and carbon ions is widely attracting interest as a potential competitor of conventional photon radiotherapy. Exquisite dose distribution of charged particles allows for a higher local control of the tumor and lower probability of damage to nearby healthy tissues. Heavy ions have presumed biological advantages rising from their high-linear energy transfer (LET) characteristics, including greater cell-killing effectiveness and reduced heterogeneity dependence of radiation response. Although these advantages are clear and supported by data, only 18.0% of proton and carbon ion radiotherapy (CIRT) facilities in Europe are treating breast cancers. This review summarizes the physical and radiobiological properties of charged particles, clinical use of particle beam for breast cancer, and suggested approaches to overcome technical and financial challenges.

The intrinsic earth magnetic field (geomagnetic field, GMF) provides an essential environmental condition for most living organisms to adapt the solar cycle by rhythmically synchronizing physiological and behavioral processes. However, hypomagnetic field (HMF) of outer space, the Moon, and the Mars differs much from GMF, which poses a critical problem to astronauts during long-term interplanetary missions. Multiple experimental works have been devoted to the HMF effects on circadian rhythm and found that HMF perturbs circadian rhythms and profoundly contributes to health problems such as sleep disorders, altered metabolic as well as neurological diseases. By systemizing the latest progress on interdisciplinary cooperation between magnetobiology and chronobiology, this review sheds light on the health effects of HMF on circadian rhythms by elaborating the underlying circadian clock machinery and molecular processes.

A numerical model for studying the time-dependent tribological performance of the floating valve-plate pair in axial piston pump is proposed. The lubrication analysis and the dynamics of the floating valve plate are taken into consideration. An additional source term is adopted into time-dependent Reynolds equation so that the model to analyze the auxiliary balance effects is set up. The boundary pressure of the kidney ports is dynamically coupled with the flow rate towards the loading. It is found that all the performance parameters fluctuate periodically and the valve-plate interface tilt has a vital impact on the tribological performances. The results obtained by the proposed model are highly detailed, and help to improve the understanding of floating valve-plate pair.

Delta-like ligand 4 is a notch ligand that is predominantly expressed in the endothelial tip cells and plays essential roles in the regulation of angiogenesis. In this study, we explored the therapeutic effects of delta-like ligand 4 gene vaccine overexpression on the syngeneic model mouse model of liver cancer and the underlying mechanisms. Mouse hepatocellular carcinoma cell line H22-H8D8 was used to generate subcutaneous syngeneic model liver cancer in Kunming mice, and the effects of recombinant plasmid pVAX1 containing delta-like ligand 4 vaccine on tumor growth was examined. Compared to controls, delta-like ligand 4 vaccination reduced syngeneic model tumor size by 70.31% (from 17.11 ± 9.30 cm 3 to 5.08 ± 2.75 cm 3 , P = .035) and tumor weight by 34.19% (from 6.26 ± 3.01 g to 4.12 ± 2.52 g, P = .102), while the mouse survival was significantly increased (from 27.7 ± 6.0 days to 33.1 ± 6.1 days, P = .047). High level of delta-like ligand 4 antibody, together with a significantly increased number of CD4 + and decreased CD8 + cells were identified in the mouse peripheral blood serum samples after delta-like ligand 4 immunization. In addition, elevated serum levels of interleukin 2, interleukin 4, and interferon γ were detected in the delta-like ligand 4–vaccinated mice when compared to the controls. Further studies have revealed increased CD31 and decreased Ki67 expression in the syngeneic model tumor tissues of vaccinated mice. Taken together, our studies suggest that delta-like ligand 4 gene vaccine can inhibit the growth of hepatocellular carcinoma in mice through inhibiting tumor angiogenesis and boosting antitumor immune responses. Hence, delta-like ligand 4 gene vaccination may be a promising strategy for the treatment of transplanted liver cancer.

The radiation exposure of individuals has been on the rise due to an increased amount of radiation use, e.g., in medicine for diagnostic imaging and treatment procedures, industrial applications including military defense activities and nuclear power plants, and in academics for educational and scientific research. Space exploration missions and space tourism are additional areas of protracted low dose exposure situations with radiation types not present on the Earth. In contrast to high doses of ionizing radiation, cancer risk assessment of the more commonly encountered or protracted radiation exposure is still under debate and uncertainty making it fuzzy area. A major challenge lies in providing a scientific basis to estimate low dose radiation carcinogenesis risks. In this review we aim, through the collected epidemiological and experimental studies' data, to address the central questions in radiological protection; including quantification of the risks and uncertainties from low doses of ionizing radiation and what is a sound scientific consensus to advise on risk perception for low dose radiation exposure.

Recent studies have demonstrated that radiation activates in situ antitumor immunity and consequently induced a synergistic effect of radiotherapy and immunotherapy. However, studies related to radiation-induced changes in immune system of tumor-bearing mice are limited, which are of great significance to improve the efficacy of radioimmunotherapy. In this study, we first established a primary lung tumor mouse model using urethane. Then part of the right lung of the mouse was exposed to X-ray irradiation with a computed tomography–guided small animal irradiator and the changes of immune cells in both peripheral blood and spleen were determined by flow cytometry. Besides, the levels of both cytokines and immunoglobulins in mouse serum were detected by a protein chip. We found that B lymphocytes increased while CD8 + T lymphocytes reduced significantly. Interleukin-3 (IL-3), IL-6, regulated upon activation, normally T-expressed, and presumably secreted factor (RANTES), and vascular endothelial growth factor (VEGF) were found to be decreased after tumor formation, and the similar results have also been observed with kappa, IgG3, IgE, IgM, and IgG2a. After irradiation, lower concentrations of IgD, kappa, and IgM were found in the serum. Our findings indicate that localized tumor irradiation caused some obvious changes like inhibiting the ability of innate immunity, and these changes may be useful in predicting prognosis.

Background/Aims: TGF-β1 mediated radiation-induced bystander effects (RIBE) have been linked with malignant transformation and tumorigenesis. However, the underlying mechanisms are not fully understood. Methods: To reveal new molecules of regulatory functions in this process, lncRNA microarray was performed to profile both lncRNA and mRNA expression patterns in human lung bronchial epithelial BEAS-2B cells treated with TGF-β1 at a concentration measured in the medium conditioned by directly irradiated BEAS-2B cells. The potential functions of the differentially expressed lncRNAs were predicted by GO and KEGG pathway analyses of their co-expressed mRNAs. Cis- and trans-regulation of the lncRNAs were analyzed and the interaction networks were constructed using Cytoscape. qRT-PCR was conducted to validate the results of microarray profiling. CCK-8 assay was employed for functional validation of 3 identified lncRNAs. Results: 224 lncRNAs were found to be dysregulated, among which 6 lncRNAs were chosen for expression validation by qRT-PCR assay. Pathway analyses showed that differentially expressed lncRNAs are highly correlated with cell proliferation, transformation, migration, etc. Trans-regulation analyses showed that the differentially expressed lncRNAs most likely participate in the pathways regulated by four transcriptional factors, FOS, STAT3, RAD21 and E2F1, which have been identified to be involved in the modulation of oncogenic transformation, cell cycle progression, genomic instability, etc. lnc-THEMIS-2 and lnc-ITGB6-4, predicted to be regulated by STAT3 and E2F1 respectively, were found to rescue the decrease of cell viability induced by TGF-β1 treatment. Conclusion: Our findings suggest that the differentially expressed lncRNAs induced by TGF-β1 play crucial roles in the oncogenic transformation and tumorigenesis, which provide a better understanding of the underlying mechanisms related to tumorigensis induced by LD/LDR radiations.

The Helium Cooled Pebble Bed (HCPB) breeding blanket, being developed by the Karlsruhe Institute of Technology (KIT) and its partners is one of the two driver blanket candidates to be selected for the European demonstration fusion power plant (EU DEMO). The in-box Loss of Coolant Accident (LOCA) is a postulated initiating event of the breeding blanket (BB) that must be accounted within the design basis. In this paper, the BB cap region is analyzed for its ability to withstand an in-box LOCA event. Initially, an assessment is performed using conventional elastic design codes for nuclear pressure vessels. However, it is thought that the elastic rules are not ‘equipped’ to assess the material damage modes which are essentially inelastic. Therefore, a non-linear inelastic analysis is further performed to better understand the damage in the material. Two predominant inelastic failure modes are thought to be relevant and addressed: exhaustion of ductility and plastic flow localization. While the design of HCPB BB has been predominantly based on the elastic design-by-analysis studies, results from the present study show that the elastic rules may be overly conservative for the given material and loading and could lead to inefficient designs. To our knowledge, this study is the first attempt to investigate the structural integrity of the European DEMO blankets under in-box LOCA conditions using the inelastic methods.

For a long time it was generally accepted that effects of ionizing radiation such as cell death, chromosomal aberrations, DNA damage, mutagenesis, and carcinogenesis result from direct ionization of cell structures, particularly DNA, or from indirect damage through reactive oxygen species produced by radiolysis of water, and these biological effects were attributed to irreparable or misrepaired DNA damage in cells directly hit by radiation. Using linear non-threshold model (LNT), possible risks from exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to higher doses of radiation. This model has been challenged by numerous observations, in which cells that were not directly traversed by the ionizing radiation exhibited responses similar to those of the directly irradiated cells. Therefore, it is nowadays accepted that the detrimental effects of ionizing radiation are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects.

Purpose. To evaluate the efficacy, feasibility, and safety of the navigation-guided endoscopy combined with deep lateral orbitotomy for removal of small tumors at the lateral orbital apex. Design. A retrospective, noncomparative case series. Methods. Retrospective analysis of ten patients (10 eyes) with small tumors at the lateral orbital apex comprised navigation-guided endoscopy combined with deep lateral orbitotomy at the Eye Hospital of Wenzhou Medical University from November 2015 to November 2017. In each case, the indication of surgery was existing or imminent visual impairment due to the tumor. The removal was believed to be complete if the mass was removed intactly during the surgery. The tumor character was confirmed by pathological examination after surgery. Patients were followed up to 3 months after surgery. Best corrected visual acuity before and after surgery was compared. Results. All tumors were completely removed by the navigation-guided endoscopic approach. The mean preoperative best corrected visual acuity was 6/15 (95% confidence interval (95% CI) 6/40–6/8.5), and the mean postoperative best corrected visual acuity was 6/10 (95% CI 6/15–6/7.5). 5 of 7 (71%) patients with vision loss gained visual improvement in different degrees after surgery, and the rest of the patients had preoperative best corrected visual acuity. Visual field of all patients also improved. 8 cavernous hemangiomas and 2 schwannomas were confirmed postoperatively by pathology. 4 patients accompanied with limitation of eye abduction, which recovered spontaneously in an average of 4 weeks. No other serious complications occurred. Conclusions. Navigation-guided endoscopy combined with deep lateral orbitotomy seems to be a feasible, efficient, and safe approach for removing small tumors at the lateral orbital apex. This trial is registered with ChiCTR1800019244.

Tuberculosis (TB) remains a significant human health issue. More effective biomarkers for use in tuberculosis prevention, diagnosis, and treatment, including markers that can discriminate between healthy individuals and those with latent infection, are urgently needed. To identify a set of such markers, we used Solexa sequencing to examine microRNA expression in the serum of patients with active disease, healthy individuals with latent TB, and those with or without prior BCG inoculation. We identified 24 microRNAs that are up-regulated (2.85-1285.93 fold) and 6 microRNAs that are down-regulated (0.003-0.11 fold) (P

Based on recent progress on moment problems, semidefinite optimization approach is proposed for estimating upper and lower bounds on linear functionals defined on solutions of linear integral equations with smooth kernels. The approach is also suitable for linear integrodifferential equations with smooth kernels. Firstly, the primal problem with smooth kernel is converted to a series of approximative problems with Taylor polynomials obtained by expanding the smooth kernel. Secondly, two semidefinite programs (SDPs) are constructed for every approximative problem. Thirdly, upper and lower bounds on related functionals are gotten by applying SeDuMi 1.1R3 to solve the two SDPs. Finally, upper and lower bounds series obtained by solving two SDPs, respectively infinitely approach the exact value of discussed functional as approximative order of the smooth kernel increases. Numerical results show that the proposed approach is effective for the discussed problems.