Susceptibility weighted magnetic resonance imaging (MRI) is sensitive to the local concentration of iron and myelin. Here, we describe a robust image processing pipeline for quantitative ...susceptibility mapping (QSM) and R2* mapping of fixed post-mortem, whole-brain data. Using this pipeline, we compare the resulting quantitative maps in brains from patients with amyotrophic lateral sclerosis (ALS) and controls, with validation against iron and myelin histology.
Twelve post-mortem brains were scanned with a multi-echo gradient echo sequence at 7T, from which susceptibility and R2* maps were generated. Semi-quantitative histological analysis for ferritin (the principal iron storage protein) and myelin proteolipid protein was performed in the primary motor, anterior cingulate and visual cortices.
Magnetic susceptibility and R2* values in primary motor cortex were higher in ALS compared to control brains. Magnetic susceptibility and R2* showed positive correlations with both myelin and ferritin estimates from histology. Four out of nine ALS brains exhibited clearly visible hyperintense susceptibility and R2* values in the primary motor cortex.
Our results demonstrate the potential for MRI-histology studies in whole, fixed post-mortem brains to investigate the biophysical source of susceptibility weighted MRI signals in neurodegenerative diseases like ALS.
Liver-specific Activities of FGF19 Require Klotho beta Lin, Benjamin C.; Wang, Manping; Blackmore, Craig ...
Journal of biological chemistry/The Journal of biological chemistry,
09/2007, Letnik:
282, Številka:
37
Journal Article
Recenzirano
Odprti dostop
Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 ...regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.
Nanostructured tin (IV) oxide (SnO2) is emerging as an ideal inorganic electron transport layer in n–i–p perovskite devices, due to superior electronic and low‐temperature processing properties. ...However, significant differences in current–voltage performance and hysteresis phenomena arise as a result of the chosen fabrication technique. This indicates enormous scope to optimize the electron transport layer (ETL), however, to date the understanding of the origin of these phenomena is lacking. Reported here is a first comparison of two common SnO2 ETLs with contrasting performance and hysteresis phenomena, with an experimental strategy to combine the beneficial properties in a bilayer ETL architecture. In doing so, this is demonstrated to eliminate room‐temperature hysteresis while simultaneously attaining impressive power conversion efficiency (PCE) greater than 20%. This approach highlights a new way to design custom ETLs using functional thin‐film coatings of nanomaterials with optimized characteristics for stable, efficient, perovskite solar cells.
SnO2 has recently emerged as an attractive n‐type layer for perovskite solar cells, with advantages of high optical transparency, high electron mobility, UV‐stabilized properties as well as low‐temperature processing. Here, a detailed study of structure and morphology of a critical aspect of these devices is reported—the electron transport layer (ETL)—demonstrating improved energy level alignment, reduced hysteresis, and interfacial recombination, which translates to enhanced device performance and stability.
BackgroundNeuroblastoma (NB) is a childhood cancer for which new treatment options are needed. The success of immune checkpoint blockade in the treatment of adult solid tumors has prompted the ...exploration of immunotherapy in NB; however, clinical evidence indicates that the vast majority of NB patients do not respond to single-agent checkpoint inhibitors. This motivates a need for therapeutic strategies to increase NB tumor immunogenicity. The goal of this study was to evaluate a new immunotherapeutic strategy for NB based on potent activation of the stimulator of interferon genes (STING) pathway.MethodsTo promote STING activation in NB cells and tumors, we utilized STING-activating nanoparticles (STING-NPs) that are designed to mediate efficient cytosolic delivery of the endogenous STING ligand, 2’3’-cGAMP. We investigated tumor-intrinsic responses to STING activation in both MYCN-amplified and non-amplified NB cell lines, evaluating effects on STING signaling, apoptosis, and the induction of immunogenic cell death. The effects of intratumoral administration of STING-NPs on CD8+ T cell infiltration, tumor growth, and response to response to PD-L1 checkpoint blockade were evaluated in syngeneic models of MYCN-amplified and non-amplified NB.ResultsThe efficient cytosolic delivery of 2’3’-cGAMP enabled by STING-NPs triggered tumor-intrinsic STING signaling effects in both MYCN-amplified and non-amplified NB cell lines, resulting in increased expression of interferon-stimulated genes and pro-inflammatory cytokines as well as NB cell death at concentrations 2000-fold to 10000-fold lower than free 2’3’-cGAMP. STING-mediated cell death in NB was associated with release or expression of several danger associated molecular patterns that are hallmarks of immunogenic cell death, which was further validated via cell-based vaccination and tumor challenge studies. Intratumoral administration of STING-NPs enhanced STING activation relative to free 2’3’-cGAMP in NB tumor models, converting poorly immunogenic tumors into tumoricidal and T cell-inflamed microenvironments and resulting in inhibition of tumor growth, increased survival, and induction of immunological memory that protected against tumor re-challenge. In a model of MYCN-amplified NB, STING-NPs generated an abscopal response that inhibited distal tumor growth and improved response to PD-L1 immune checkpoint blockade.ConclusionsWe have demonstrated that activation of the STING pathway, here enabled by a nanomedicine approach, stimulates immunogenic cell death and remodels the tumor immune microenvironment to inhibit NB tumor growth and improve responses to immune checkpoint blockade, providing a multifaceted immunotherapeutic approach with potential to enhance immunotherapy outcomes in NB.
Amantamide B (
) is a new linear nonapeptide analogue of the cyanobacterial natural product amantamide A (
), and both have methyl ester and butanamide termini. These compounds were discovered in ...this study from the organic extract of a tropical marine filamentous cyanobacterium,
sp., collected around the Paracel Islands in the South China Sea. The use of LC-MS/MS molecular networking for sample prioritization and as an analytical dereplication tool facilitated the targeted isolation of
and
. These molecules were characterized by spectroscopy and spectrometry, and configurational assignments were determined using chemical degradation and chiral-phase HPLC analysis. Compounds
and
modulated spontaneous calcium oscillations without notable cytotoxicity at 10 μM in short duration in vitro testing on primary cultured neocortical neurons, a model system that evaluates neuronal excitability and/or the potential activity on Ca
signaling. Both molecules were also found to be moderately cytotoxic in longer duration bioassays, with in vitro IC
values of 1-10 μM against CCRF-CEM human T lymphoblastoid cells and U937 human histiocytic lymphoma cells. These formerly undiscovered bioactivities of known compound
expand upon its previously reported function as a selective CXCR7 agonist among 168 GPCR targets.
China’s CO2 emissions exports embodied in international trade has recently attracted more attention and raises questions on the liability and responsibility for environmental costs associated with ...Chinese-produced goods. Given that embodied emissions exports and imports are normal phenomena during international trade, the key question focuses on China’s reduction of embodied emissions exports via trade restructuring. A trade restructuring optimization model combined with input-output analysis and multi-objective programming was established in this study, in order to analyze the maximum volume of embodied emissions reduction within bearable cost constraints. The results suggest that the trade-off cost for China to reduce embodied emissions exports is very high. Additionally, the net exports of China’s embodied CO2 emissions under a reasonable scenario can only be reduced by 3.26%. Previous policy suggestions on import-export structure adjustments have limited effects on the reduction of China’s embodied emission exports, and unemployment is an important constraint on embodied CO2 emissions export reduction. Even so, China can still take advantage of various positive factors that have emerged in recent years to improve the industrial and energy consumption structures given that the increasing trend of China’s embodied CO2 emission exports has already changed gradually.
Chemical investigation of
sp. NBUF088, associated with an
sp. sponge located at an 84 m deep mesophotic zone, led to the discovery of two new heptaketides, named irpetones A (
) and B (
). Their ...structures were identified by analysis of spectroscopic data and quantum-chemical calculations. Compound
exhibited inhibition against the receptor activator of NF-κB ligand-induced osteoclastogenesis in bone marrow monocytes with an IC
of 6.3 ± 0.2 μM, causing no notable cytotoxicity. It was also determined that
inhibited the phosphorylation of ERK1/2-JNK1/2-p38 MAPKs and the nuclear translocation of NF-κB, consequently suppressing the activation of MAPK and NF-κB signaling pathways induced by the NF-κB ligand.
As a common policy tool for reducing the cost of achieving the Renewable Portfolio Standard (RPS) targets, Renewable Energy Certificate (REC) trade can also exacerbate distributional inequity in ...provincial renewable electricity consumption. In this study, two types of corrective regulations –taxation and quotas on REC importing were proposed to pursue the equity-efficient trade-off. The energy, economic, and equity impacts of these corrective regulations were analyzed by applying a multi-region multi-market equilibrium model to China as a case study. The results verified that a free trade REC market can increase distributional inequity, while both import taxation and import quotas can reduce inequity. Compared to the electricity price premium for renewable energy and voluntary green certificate prices, the social cost of implementing these corrective regulations are within the public's willingness-to-pay. Moreover, the cost curve of increasing equity using the two corrective regulations on REC trade were obtained. Import taxation is found to be more cost-efficient, and therefore it should be the prior policy choice for China's central government comparing with import quotas in designing REC trade mechanisms.
•The regional inequity of renewable energy development under RPS with free REC trade is verified.•Taxation and quotas, two regulations on REC trade are proposed to corrective the inequity.•An equilibrium model is developed and applied to test the energy-economic-equity impacts of the corrective regulations.•The import taxation is proved to be a more cost-efficient corrective regulation than import quotas.
Utility mining is a new development of data mining technology. Among utility mining problems, utility mining with the itemset share framework is a hard one as no anti-monotonicity property holds with ...the interestingness measure. Prior works on this problem all employ a two-phase, candidate generation approach with one exception that is however inefficient and not scalable with large databases. The two-phase approach suffers from scalability issue due to the huge number of candidates. This paper proposes a novel algorithm that finds high utility patterns in a single phase without generating candidates. The novelties lie in a high utility pattern growth approach, a lookahead strategy, and a linear data structure. Concretely, our pattern growth approach is to search a reverse set enumeration tree and to prune search space by utility upper bounding. We also look ahead to identify high utility patterns without enumeration by a closure property and a singleton property. Our linear data structure enables us to compute a tight bound for powerful pruning and to directly identify high utility patterns in an efficient and scalable way, which targets the root cause with prior algorithms. Extensive experiments on sparse and dense, synthetic and real world data suggest that our algorithm is up to 1 to 3 orders of magnitude more efficient and is more scalable than the state-of-the-art algorithms.
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