| 1. |
- Zeng, Xiao, et al.
(författare)
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A scoping study on remelting process of a debris bed in the lower head of reactor pressure vessel
- 2023
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Ingår i: Annals of Nuclear Energy. - : Elsevier BV. - 0306-4549 .- 1873-2100. ; 189
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Tidskriftsartikel (refereegranskat)abstract
- Coolability and retention of core melt (corium) in the lower head of reactor pressure vessel (RPV) has been accepted as a severe accident management strategy to maintain the reactor pressure vessel (RPV) integrity of a light water reactor. To qualify the in-vessel melt retention strategy, lots of studies have been performed to investigate the natural convection heat transfer of a melt pool in the lower head. However, little work has been attributed to the precursory phase of the melt pool, i.e., the remelting process of a debris bed which is formed in the lower head at the very beginning of corium relocation from the core the lower head. The present study is motivated to conduct an experimental study on the debris remelting process. For this purpose, a dedicated test facility named COREM (COrium REMelting) is conceived and constructed, which features internal heating of electromagnetic induction and visualization of debris remelting dynamics. The test section is a semicircular vessel representing a slice of scaled-down RPV lower head, whose front and back walls are made of transparent tempered glass which facilitate visualization and induction heating of the debris bed. Fiber probes with multiple optical temperature sensors are mounted in the semicircular wall of the test section to measure its temperature distribution. In the scoping test, n-octanol and Wood's metal are selected as the simulant materials of metallic and oxidic components of corium, respectively, and their particles ware loaded in the test section to form a debris bed. This paper presents the first two scoping tests which have been performed with the COREM facility so far, under different mixing ratios of two debris materials. The measured data include the photography of debris remelting processes and the temperatures in the debris bed and the semicircular wall. Based on the temperature distributions, heat flux profile along the semicircular vessel wall is also estimated. The scoping tests well reproduce the dynamic process of debris remelting, with two distinct stages of fusion of n-octanol and Wood's metal, i.e., melting successively from low to high melting-point debris particles. During the remelting process, the vessel wall temperatures increase with the polar angle firstly and then decrease gradually, leading to the highest temperature appearing in the middle of the lower layer of the stratified molten pool which is finally formed.
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| 2. |
- Liu, Lihui, et al.
(författare)
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Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity
- 2023
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Ingår i: Cell Reports Medicine. - : Cell Press. - 2666-3791. ; 4:10
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Tidskriftsartikel (refereegranskat)abstract
- Immunophenotyping of the tumor microenvironment (TME) is essential for enhancing immunotherapy effi-cacy. However, strategies for characterizing the TME exhibit significant heterogeneity. Here, we show that endoplasmic reticular oxidoreductase-1a (ERO1A) mediates an immune-suppressive TME and attenuates the response to PD-1 blockade. Ablation of ERO1A in tumor cells substantially incites anti-tumor T cell im-munity and promotes the efficacy of aPD-1 in therapeutic models. Single-cell RNA-sequencing analyses confirm that ERO1A correlates with immunosuppression and dysfunction of CD8+ T cells along anti-PD-1 treatment. In human lung cancer, high ERO1A expression is associated with a higher risk of recurrence following neoadjuvant immunotherapy. Mechanistically, ERO1A ablation impairs the balance between IRE1a and PERK signaling activities and induces lethal unfolded protein responses in tumor cells undergoing endoplasmic reticulum stress, thereby enhancing anti-tumor immunity via immunogenic cell death. These findings reveal how tumor ERO1A induces immunosuppression, highlighting its potential as a therapeutic target for cancer immunotherapy.
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| 3. |
- Luo, Yifei, et al.
(författare)
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Technology Roadmap for Flexible Sensors
- 2023
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Ingår i: ACS Nano. - : American Chemical Society. - 1936-0851 .- 1936-086X. ; 17:6, s. 5211-5295
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Forskningsöversikt (refereegranskat)abstract
- Humans rely increasingly on sensors to address grand challenges and to improve quality of life in the era of digitalization and big data. For ubiquitous sensing, flexible sensors are developed to overcome the limitations of conventional rigid counterparts. Despite rapid advancement in bench-side research over the last decade, the market adoption of flexible sensors remains limited. To ease and to expedite their deployment, here, we identify bottlenecks hindering the maturation of flexible sensors and propose promising solutions. We first analyze challenges in achieving satisfactory sensing performance for real-world applications and then summarize issues in compatible sensor-biology interfaces, followed by brief discussions on powering and connecting sensor networks. Issues en route to commercialization and for sustainable growth of the sector are also analyzed, highlighting environmental concerns and emphasizing nontechnical issues such as business, regulatory, and ethical considerations. Additionally, we look at future intelligent flexible sensors. In proposing a comprehensive roadmap, we hope to steer research efforts towards common goals and to guide coordinated development strategies from disparate communities. Through such collaborative efforts, scientific breakthroughs can be made sooner and capitalized for the betterment of humanity.
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| 4. |
- Weiffenbach, Julia E., et al.
(författare)
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Unraveling the mechanisms and implications of a stronger mid-Pliocene Atlantic Meridional Overturning Circulation (AMOC) in PlioMIP2
- 2023
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Ingår i: Climate of the Past. - : COPERNICUS GESELLSCHAFT MBH. - 1814-9324 .- 1814-9332. ; 19:1, s. 61-85
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Tidskriftsartikel (refereegranskat)abstract
- The mid-Pliocene warm period (3.264-3.025 Ma) is the most recent geological period in which the atmospheric CO2 concentration was approximately equal to the concentration we measure today (ca. 400 ppm). Sea surface temperature (SST) proxies indicate above-average warming over the North Atlantic in the mid-Pliocene with respect to the pre-industrial period, which may be linked to an intensified Atlantic Meridional Overturning Circulation (AMOC). Earlier results from the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2) show that the ensemble simulates a stronger AMOC in the mid-Pliocene than in the pre-industrial. However, no consistent relationship between the stronger mid-Pliocene AMOC and either the Atlantic northward ocean heat transport (OHT) or average North Atlantic SSTs has been found. In this study, we look further into the drivers and consequences of a stronger AMOC in mid-Pliocene compared to pre-industrial simulations in PlioMIP2. We find that all model simulations with a closed Bering Strait and Canadian Archipelago show reduced freshwater transport from the Arctic Ocean into the North Atlantic. This contributes to an increase in salinity in the subpolar North Atlantic and Labrador Sea that can be linked to the stronger AMOC in the mid-Pliocene. To investigate the dynamics behind the ensembles variable response of the total Atlantic OHT to the stronger AMOC, we separate the Atlantic OHT into two components associated with either the overturning circulation or the wind-driven gyre circulation. While the ensemble mean of the overturning component is increased significantly in magnitude in the mid-Pliocene, it is partly compensated by a reduction in the gyre component in the northern subtropical gyre region. This indicates that the lack of relationship between the total OHT and AMOC is due to changes in OHT by the subtropical gyre. The overturning and gyre components should therefore be considered separately to gain a more complete understanding of the OHT response to a stronger mid-Pliocene AMOC. In addition, we show that the AMOC exerts a stronger influence on North Atlantic SSTs in the mid-Pliocene than in the pre-industrial, providing a possible explanation for the improved agreement of the PlioMIP2 ensemble mean SSTs with reconstructions in the North Atlantic.
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| 5. |
- Bayraktar, Abdulahad, et al.
(författare)
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Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer's disease patients
- 2023
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Ingår i: Journal of Translational Medicine. - : BMC. - 1479-5876 .- 1479-5876. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDespite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer's patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer's studies.MethodsHere, we investigated central co-expressed genes upregulated in Alzheimer's disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene's estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved.ResultsWe identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood-brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool.ConclusionsThis study method effectively identified an Alzheimer's disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer's disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer's patients.
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| 6. |
- Graves, Occam Kelly, et al.
(författare)
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Discovery of drug targets and therapeutic agents based on drug repositioning to treat lung adenocarcinoma
- 2023
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Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier BV. - 0753-3322 .- 1950-6007. ; 161
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lung adenocarcinoma (LUAD) is the one of the most common subtypes in lung cancer. Although various targeted therapies have been used in the clinical practice, the 5-year overall survival rate of patients is still low. Thus, it is urgent to identify new therapeutic targets and develop new drugs for the treatment of the LUAD patients. Methods: Survival analysis was used to identify the prognostic genes. Gene co-expression network analysis was used to identify the hub genes driving the tumor development. A profile-based drug repositioning approach was used to repurpose the potentially useful drugs for targeting the hub genes. MTT and LDH assay were used to measure the cell viability and drug cytotoxicity, respectively. Western blot was used to detect the expression of the proteins. Findings: We identified 341 consistent prognostic genes from two independent LUAD cohorts, whose high expression was associated with poor survival outcomes of patients. Among them, eight genes were identified as hub genes due to their high centrality in the key functional modules in the gene-co-expression network analysis and these genes were associated with the various hallmarks of cancer (e.g., DNA replication and cell cycle). We performed drug repositioning analysis for three of the eight genes (CDCA8, MCM6, and TTK) based on our drug repositioning approach. Finally, we repurposed five drugs for inhibiting the protein expression level of each target gene and validated the drug efficacy by performing in vitro experiments. Interpretation: We found the consensus targetable genes for the treatment of LUAD patients with different races and geographic characteristics. We also proved the feasibility of our drug repositioning approach for the development of new drugs for disease treatment.
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| 7. |
- Guo, Donglin, et al.
(författare)
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Highly restricted near-surface permafrost extent during the mid-Pliocene warm period
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Accurate understanding of permafrost dynamics is critical for evaluating and mitigating impacts that may arise as permafrost degrades in the future; however, existing projections have large uncertainties. Studies of how permafrost responded historically during Earth's past warm periods are helpful in exploring potential future permafrost behavior and to evaluate the uncertainty of future permafrost change projections. Here, we combine a surface frost index model with outputs from the second phase of the Pliocene Model Intercomparison Project to simulate the near-surface (similar to 3 to 4 m depth) permafrost state in the Northern Hemisphere during the mid-Pliocene warm period (mPWP, similar to 3.264 to 3.025 Ma). This period shares similarities with the projected future climate. Constrained by proxy-based surface air temperature records, our simulations demonstrate that near-surface permafrost was highly spatially restricted during the mPWP and was 93 +/- 3% smaller than the preindustrial extent. Near-surface permafrost was present only in the eastern Siberian uplands, Canadian high Arctic Archipelago, and northernmost Greenland. The simulations are similar to near-surface permafrost changes projected for the end of this century under the SSP5-8.5 scenario and provide a perspective on the potential permafrost behavior that may be expected in a warmer world.
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| 8. |
- Jin, Han, et al.
(författare)
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Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1, s. 5417-
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Tidskriftsartikel (refereegranskat)abstract
- Cell lines are valuable resources as model for human biology and translational medicine. It is thus important to explore the concordance between the expression in various cell lines vis-à-vis human native and disease tissues. In this study, we investigate the expression of all human protein-coding genes in more than 1,000 human cell lines representing 27 cancer types by a genome-wide transcriptomics analysis. The cell line gene expression is compared with the corresponding profiles in various tissues, organs, single-cell types and cancers. Here, we present the expression for each cell line and give guidance for the most appropriate cell line for a given experimental study. In addition, we explore the cancer-related pathway and cytokine activity of the cell lines to aid human biology studies and drug development projects. All data are presented in an open access cell line section of the Human Protein Atlas to facilitate the exploration of all human protein-coding genes across these cell lines.
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| 9. |
- Li, Xiangyu, et al.
(författare)
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The acute effect of different NAD+ precursors included in the combined metabolic activators
- 2023
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 205, s. 77-89
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Tidskriftsartikel (refereegranskat)abstract
- NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions.
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| 10. |
- Liao, Xinmeng, et al.
(författare)
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Open MoA : revealing the mechanism of action (MoA) based on network topology and hierarchy
- 2023
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 39:11
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Many approaches in systems biology have been applied in drug repositioning due to the increased availability of the omics data and computational biology tools. Using a multi-omics integrated network, which contains information of various biological interactions, could offer a more comprehensive inspective and interpretation for the drug mechanism of action (MoA). RESULTS: We developed a computational pipeline for dissecting the hidden MoAs of drugs (Open MoA). Our pipeline computes confidence scores to edges that represent connections between genes/proteins in the integrated network. The interactions showing the highest confidence score could indicate potential drug targets and infer the underlying molecular MoAs. Open MoA was also validated by testing some well-established targets. Additionally, we applied Open MoA to reveal the MoA of a repositioned drug (JNK-IN-5A) that modulates the PKLR expression in HepG2 cells and found STAT1 is the key transcription factor. Overall, Open MoA represents a first-generation tool that could be utilized for predicting the potential MoA of repurposed drugs and dissecting de novo targets for developing effective treatments. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://github.com/XinmengLiao/Open_MoA.
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