Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the ...tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast, the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor‐derived nanovesicles capable of altering gene expression and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles and exosomes that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells and can transmit a functional transgene. The microRNA (miRNA) content of these exosomes was examined, and a subset highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase‐1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNAs. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for intercellular modulation. We show that HCC cell‐derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells. Conclusion: Exosome‐mediated miRNA transfer is an important mechanism of intercellular communication in HCC cells. These observations identify a unique intercellular mechanism that could potentially contribute to local spread, intrahepatic metastases, or multifocal growth in HCC. (HEPATOLOGY 2011;)
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High-entropy alloys (HEAs) have received much attention for the development of nuclear materials because of their excellent irradiation tolerance. In the present study, the generation and evolution ...of irradiation-induced defects in the NiCoCrFe HEA were investigated by molecular dynamics (MD) simulations to understand the mechanisms of its irradiation tolerance compared with bulk Ni. The displacement cascades were simulated for the energies of primary knock-on atoms (PKA) ranging from 10 to 50 keV to understand the irradiation resistance in HEAs. In general, there are more displaced atoms produced in the thermal spike phase, but fewer defects survived at the end of the cascades in the NiCoCrFe alloy than in Ni. Both interstitial and vacancy clusters increase in size or number with increasing PKA energy in both materials, but they do so more slowly in the NiCoCrFe HEA. The delayed damage accumulations in the NiCoCrFe HEA are attributed to the high defect recombination caused by the following two mechanisms. First, the enhanced thermal spike and the low thermal conductivity of HEAs for heat dissipation result in the higher efficiency of defect recombination. Furthermore, the substantially small binding energies of interstitial loops in the NiCoCrFe HEA, as compared with those in Ni, are responsible for the delayed interstitial clustering in the NiCoCrFe HEA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mesoscale weather systems are responsible for numerous natural disasters, such as damaging winds, blizzards and flash flooding. A fundamental understanding of the underlying dynamics involved in ...these weather systems is essential in forecasting their occurrence. This 2007 book provides a systematic approach to this subject. The opening chapters introduce the basic equations governing mesoscale weather systems and their approximations. The subsequent chapters cover four major areas of mesoscale dynamics: wave dynamics, moist convection, front dynamics and mesoscale modelling. This is an ideal book on the subject for researchers in meteorology and atmospheric science. With over 100 problems, and password-protected solutions available to instructors at www.cambridge.org/9780521808750, this book could also serve as a textbook for graduate students. Modelling projects, providing hands-on practice for building simple models of stratified fluid flow from a one-dimensional advection equation, are also described.
Concentration of extracellular vesicles (EVs) from biological fluids in a scalable and reproducible manner represents a major challenge. This study reports the use of tangential flow filtration (TFF) ...for the highly efficient isolation of EVs from large volumes of samples. When compared to ultracentrifugation (UC), which is the most widely used method to concentrate EVs, TFF is a more efficient, scalable, and gentler method. Comparative assessment of TFF and UC of conditioned cell culture media revealed that the former concentrates EVs of comparable physicochemical characteristics, but with higher yield, less single macromolecules and aggregates (<15 nm in size), and improved batch-to-batch consistency in half the processing time (1 h). The TFF protocol was then successfully implemented on fluids derived from patient lipoaspirate. EVs from adipose tissue are of high clinical relevance, as they are expected to mirror the regenerative properties of the parent cells.
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In 2009, Typhoon Morakot delivered high intensity rainfall and triggered many sites of large landslide, which projected areas were larger than 10,000m2 from the satellite image, especially in ...southern Taiwan. According to DTM analysis, the material volume of the large landslide in Butangbunasi River was more than four times larger than that of the nearly famous landslide disaster in Hsiaolin village. Nevertheless, the different movement of these two large landslides led to different disaster impacts. Based on literatures and field works, the large Hsiaolin landslide was a catastrophic landslide, which had high velocity and less energy loss in the kinematic process. The source area of the large landslide in the Butangbunasi River, on the other hand, was composed of several landslide events, and the kinetic energy dissipated when the landslide materials attained to riverbed in sequence. In this study, we divided the Butangbunasi River large landslide into five slope units, namely A, B, C, D and E landslide events, to recognize the mechanism of the large landslide, and the simulation by using the Particle Flow Code 3D (PFC3D), which is based on the discrete element method, provided the kinematic process of the large landslide in the Butangbunasi River. It is noticed that most of the initial energy dissipated during the movement which the fist happening landslide event counteracted the crash of the follow-up events, and the residual energy gradually declined by the collision interaction of landslide blocks until the end of the large landslide. The result helps to reconstruct the evolution of the large landslide from small-scale landslide events and contributes to predict the affected region of the disaster. It also reveals that even though the impact of the large landslide is reduced by sequent small-scale landslide events, there still remain secondary disasters, such as landslide dam, which show a high potential risk in the river valley and midstream.
•The large landslide, which was formed by several small-scale landslide events, was investigated in the Butangbunasi River.•The evolution of large landslide was reconstructed by using PFC3D model.•The composition and geometry of the survival landslide dam can be recognized by the simulation result.•The subsequent disasters should be noticed in the midstream and the confluence.
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In the process of tunnel blasting excavation, radial cracks could be induced. To investigate the effect of loading rates on crack propagation velocity and rock initiation toughness, a new cracked ...tunnel specimen was proposed in this paper, and drop weight impact experiments were conducted. The crack propagation velocity and crack initiation time were measured by using crack propagation gauges (CPGs), and the measuring results were applied in the determination of initiation toughness. In order to validate the effectiveness of the cracked tunnel specimens and to predict the test results, finite difference numerical models were established by using AUTODYN code. The simulation results of crack propagation speeds and delayed fracture time generally agree with the experimental results, and crack arrest phenomena occur during crack propagation. The dynamic stress intensity factors (SIFs) were calculated by using ABAQUS code, and the initiation toughness under different loading rates was obtained by using experimental-numerical method. The studying results show that crack propagation speeds and initiation toughness increase with loading rates, but as the loading rate is larger than a certain value, the crack speeds tend toward a stable value; Delayed fracture time decreases with the increase of loading rates, and as the loading rate is larger than a certain value, it tends toward a stable value.
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Biodegradable plastics, as alternatives to conventional plastics, are increasingly used, but their interactions with organic pollutants are still unknown. In this study, the sorption and desorption ...behaviors on a type of biodegradable plastic−poly(butylene adipate co-terephtalate) (PBAT) were investigated, and at the same time two types of conventional plastics−polyethylene (PEc and PEv) and polystyrene (PS) were used for comparison. Phenanthrene (PHEN) was chosen as one of representative organic pollutants. Results indicated that the sorption and desorption capacities of PBAT were not only higher than those of the other types of microplastics, but also higher than those of carbonaceous geosorbents. The surface area normalized results illustrated that sorption and desorption of the microplastics were positively correlated with their abundance of rubbery subfraction. The sorption kinetic results showed that the sorption rates of PBAT and PEc were higher than PEv and PS. The effects of water chemistry factors including salinity, dissolved organic matter and Cu2+ ion on the sorption process displayed the same trend, but the degrees of influence on the four microplastics differed. The degrees of influence were mainly dependent on the abundance of rubbery subfraction for microplastics. These findings indicate that the biodegradable poly(butylene adipate co-terephtalate) microplastics are actually stronger vectors than the conventional microplastics, and crystallization characteristics of the microplastics have great influences on the vector effect.
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•Biodegradable microplastics sorbed/desorbed more PHEN than conventional ones.•Sorption/desorption capacities depended on the content of rubbery subfraction.•Plastic additives didn't alter the microplastics adsorption process.•High salinity and low DOM strengthen the sorption of PHEN onto microplastics.
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Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In ...this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.
This research aimed to investigate the immunomodulatory effects of phosphorylated
polysaccharides (pRCPS) in immunosuppressed mice, improving their cellular and humoral immune function. Our results ...showed that pRCPS increased serum immunoglobulin (IgG, IgA, IgM) concentrations significantly, enhanced splenocyte proliferation, and the thymus and spleen indices. pRCPS also promoted phagocytosis in peritoneal macrophages and enhanced cytokine (IFN-γ, IL-2, -4, -5, -6, and -10) serum levels. Importantly, pRCPS increased the proportions of selected T cell subpopulations (CD3
, CD4
, and the CD4
to CD8
ratio). Our results revealed that phosphorylation of the polysaccharides promoted their immune-enhancing effects. Thus, pRCPS can enhance cellular and humoral immunity and could be used as an immune-enhancing agent to overcome cyclophosphamide (CY)-induced immunosuppression.
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How hexanucleotide GGGGCC (G
C
) repeat expansions in
cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express ...poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G
C
repeats. The expression of green fluorescent protein-conjugated (PR)
(a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of
-associated FTD and ALS.
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