Nitric oxide is a versatile mediator formed by enzymes called nitric oxide synthases. It has numerous homeostatic functions and important roles in inflammation. Within the inflamed brain, microglia ...and astrocytes produce large amounts of nitric oxide during inflammation. Excessive nitric oxide causes neuronal toxicity and death and mesenchymal stem cells can be used as an approach to limit the neuronal damage caused by neuroinflammation. Mesenchymal stem cell therapy ameliorates inflammation and neuronal damage in disease models of Alzheimer’s disease, Parkinson’s disease, and other neuroinflammatory disorders. Interestingly, we have reported that in vitro, mesenchymal stem cells themselves contribute to a rise in nitric oxide levels through microglial cues. This may be an undesirable effect and highlights a possible need to explore acellular approaches for mesenchymal stem cell therapy in the central nervous system.
Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, ...emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.
Changes in the spatiotemporal dynamics of the global water cycle will constitute some of the greatest challenges to socioeconomic‐environmental well‐being in a warming world. Large multimodel, ...multiscenario intercomparisons such as the Coupled Model Intercomparison Project Phase 5 (CMIP5) experiment support our best estimates of projected climate change and associated uncertainty thereof. It is important to continually reevaluate how this information is synthesized and communicated and at what point it becomes actionable. In this study, we demonstrate a systematic and holistic framework for synthesizing multimodel ensemble projections of water availability at large river basin scale—the scale at which water resources are both managed and monitored. We identify statistically significant shifts in mean water availability at annual and monthly scales, its interannual variations, and its relative seasonality, as computed from CMIP5 historical (1976–2005) and Representative Concentration Pathway 8.5 (2070–2099) scenario multimodel ensemble output. Water availability is addressed separately through the lens of meteorologists (precipitation), hydrologists (runoff), and agriculturalists (precipitation minus evapotranspiration). We illustrate limitations in CMIP5 model representativeness through comparisons of atmosphere‐only model (Atmospheric Model Intercomparison Project) output against observational best estimates. And we find that warming‐induced shifts in water availability projected by CMIP5 carbon‐cycling Earth system models are comparatively less substantial than those projected by traditional general circulation models. As we show, knowing the seasonality of both projected changes and of the biased model background climatology onto which they are imposed is paramount to ensuring proper interpretation and ascribing confidence.
Key Points
CMIP5 projections of significant subseasonal changes in water availability are often overlooked and underestimated
Carbon‐cycling Earth system models project 23% fewer significant shifts in future water availability than general circulation models
The magnitude of model errors, as quantified through observational comparison, may preclude the credibility of projections for some basins
Monitoring voltage dynamics in defined neurons deep in the brain is critical for unraveling the function of neuronal circuits but is challenging due to the limited performance of existing tools. In ...particular, while genetically encoded voltage indicators have shown promise for optical detection of voltage transients, many indicators exhibit low sensitivity when imaged under two-photon illumination. Previous studies thus fell short of visualizing voltage dynamics in individual neurons in single trials. Here, we report ASAP2s, a novel voltage indicator with improved sensitivity. By imaging ASAP2s using random-access multi-photon microscopy, we demonstrate robust single-trial detection of action potentials in organotypic slice cultures. We also show that ASAP2s enables two-photon imaging of graded potentials in organotypic slice cultures and in
. These results demonstrate that the combination of ASAP2s and fast two-photon imaging methods enables detection of neural electrical activity with subcellular spatial resolution and millisecond-timescale precision.
We present a clear case study on the occurrence of two successive X-class flares, including a decade-class flare (X9.3) and two coronal mass ejections (CMEs) triggered by shearing motion and sunspot ...rotation in active region NOAA 12673 on 2017 September 6. A shearing motion between the main sunspots with opposite polarities began on September 5 and lasted even after the second X-class flare on September 6. Moreover, the main sunspot with negative polarity rotated around its umbral center, and another main sunspot with positive polarity also exhibited a slow rotation. The sunspot with negative polarity at the northwest of the active region also began to rotate counterclockwise before the onset of the first X-class flare, which is related to the formation of the second S-shaped structure. The successive formation and eruption of two S-shaped structures were closely related to the counterclockwise rotation of the three sunspots. The existence of a flux rope is found prior to the onset of two flares by using nonlinear force-free field extrapolation based on the vector magnetograms observed by Solar Dynamics Observatory/Helioseismic and Magnetic Image. The first flux rope corresponds to the first S-shaped structures mentioned above. The second S-shaped structure was formed after the eruption of the first flux rope. These results suggest that a shearing motion and sunspot rotation play an important role in the buildup of the free energy and the formation of flux ropes in the corona that produces solar flares and CMEs.
We report a brittle Mg-based bulk metallic glass which approaches the ideal brittle behavior. However, a dimple structure is observed at the fracture surface by high resolution scanning electron ...microscopy, indicating some type of "ductile" fracture mechanism in this very brittle glass. We also show, from the available data, a clear correlation between the fracture toughness and plastic process zone size for various glasses. The results indicate that the fracture in brittle metallic glassy materials might also proceed through the local softening mechanism but at different length scales.
Leptin alleviates metabolic conditions such as insulin resistance and obesity, although the precise mechanism of action is unclear. Mitochondrial fusion/fission states affect energy balance, but the ...association between mitochondrial fusion and lipid metabolism is also unknown. The aim of this study was to determine whether mitochondrial fusion/fission state regulates lipid accumulation and to understand the role of leptin in mitochondrial function and its mechanism of action in metabolic regulation.
Primary mouse hepatocytes were isolated from C57BL/6J mice and treated with leptin (25 ng ml(-1)) for 3 days before determinations of mitochondrial morphology and fatty acid accumulation. Hyperglycemia in C57BL/6J mice was induced by providing a 30% fructose-rich diet (FRD) for 6 months, followed by intraperitoneal injections of leptin (1 mg kg(-1) per body weight) for 6 weeks (twice per week).
Leptin triggered mitochondrial fusion and alleviated high glucose-induced fatty acid accumulation in primary hepatocytes by promoting mitochondrial fusion-associated transcription factor peroxisome proliferative-activated receptor-α and co-activator peroxisome proliferative-activated receptor-γ co-activator (PGC)-1α. In turn, these activate the fusion protein mitofusin 1 (Mfn-1). RNA silencing of Mfn-1 or PGC-1 blocked the inhibitory effect of leptin. Leptin treatment also elevated liver Mfn-1 and PGC-1α and improved lipid profiles in FRD mice.
Mitochondrial fusion has a critical role in alleviating hepatic fatty acid accumulation. Leptin switches mitochondrial morphology via a PGC-1α-dependent pathway to improve hyperlipidemia.
Heart growth is tightly controlled so that the heart reaches a predetermined size. Fetal heart growth occurs through cardiomyocyte proliferation, whereas postnatal heart growth involves primarily ...physiological cardiomyocyte hypertrophy. The Hippo kinase cascade is an important regulator of organ growth. A major target of this kinase cascade is YAP1, a transcriptional coactivator that is inactivated by Hippo kinase activity. Here, we used both genetic gain and loss of Yapl function to investigate its role in regulating proliferative and physiologic hypertrophie heart growth. Fetal Yap1 inactivation caused marked, lethal myocardial hypoplasia and decreased cardiomyocyte proliferation, whereas fetal activation of YAP1 stimulated cardiomyocyte proliferation. Enhanced proliferation was particularly dramatic in trabecular cardiomyocytes that normally exit from the cell cycle. Remarkably, YAP1 activation was sufficient to stimulate proliferation of postnatal cardiomyocytes, both in culture and in the intact heart. A dominant negative peptide that blocked YAP1 binding to TEAD transcription factors inhibited YAP1 proliferative activity, indicating that this activity requires YAP 1-TEAD interaction. Although Yap1 was a critical regulator of cardiomyocyte proliferation, it did not influence physiological hypertrophie growth of cardiomyocytes, because postnatal Yap1 gain or loss of function did not significantly alter cardiomyocyte size. These studies demonstrate that Yap1 is a crucial regulator of cardiomyocyte proliferation, cardiac morphogenesis, and myocardial trabeculation. Activation of Yap1 in postnatal cardiomyocytes may be a useful strategy to stimulate cardiomyocyte expansion in therapeutic myocardial regeneration.
Remote sensing is a useful tool for observing the water cycle. However, combining remote sensing products over any major river basin will result in a residual error in the overall water balance. ...Previous studies have either quantified this error without correcting it, or have merged observations together with land surface models (LSMs) to produce a single “best” estimate of the water balance. Here, we present a new approach in which combinations of remote sensing and in situ observations are constrained to enforce water balance closure. Rather than a single estimate, this produces an ensemble of unique water balance estimates intended to characterize uncertainty and to avoid biases implicit in LSMs. We evaluate three techniques of varying complexity to enforce water balance closure for individual ensemble members over 24 global basins from Oct. 2002 - Dec. 2014, resulting in as many as 60 realizations of the monthly water budget, contingent upon data availability. Compared with a published climate data record, the ensemble shows strong agreement for precipitation, evapotranspiration and changes in storage (R2: 0.91–0.95), with less agreement for streamflow (R2: 0.42–0.47), which may be indicative of LSM biases in the climate data record. Water balance residual errors resulting from combinations of raw products vary significantly (p < 0.001) with latitude, with a tendency for positive biases for low- and mid-latitude basins, and negative biases elsewhere. Overall, residual errors are equivalent to 15% of total precipitation when averaged across all data products and basins. This study shows that closure constraints provide additional value outside of closing the water budget, including reduction of uncertainty and transfer of closure constraints in time to provide skillful estimates of mean annual basin discharge. We also showed that a simpler closure technique, proportional redistribution, performed better than more complex ones in decreasing uncertainty and for transfer through time to estimate basin discharge when a rigorous analysis of errors for each data product is not accounted for. This observation-based dataset is distinct from modeled estimates and therefore has the potential to preserve important information of anthropogenic effects on the water balance.
•We develop ensembles of the remotely sensed water budget over 24 global basins.•Water imbalance errors vary between 0.7% and 30% of precipitation by study basin.•Closure constraints are applied to realizations of the remotely sensed water budget.•The remotely sensed ensemble agrees with a published climate data record.•There are systematic biases present in the remotely sensed water budget.
Objective
The aims of this study were to examine the factor structure and reliability of the multidimensional Reproductive Concerns After Cancer (RCAC) scale in a sample of female cancer survivors ...during their reproductive years, younger than age 45.
Methods
Female reproductive‐aged survivors (N = 238; current age, 18 to 44 y) with a variety of cancer diagnoses completed a web‐based survey that included the RCAC scale. Three structural models were examined via confirmatory factor analysis: (a) one‐factor, (b) higher‐order with one second‐order factor and six first‐order factors, and (c) oblique six‐factor. Reliability was examined using omega total and Revelle omega total.
Results
Only the oblique six‐factor model of the RCAC scale fits well. Omega total and Revelle omega total estimates for all of the six three‐item subscales were in the nearly satisfactory to good range (.66 to.87).
Conclusions
The RCAC scale was found to have satisfactory factor structure and reliability when measuring a range of reproductive concerns experienced by female reproductive‐aged survivors. The RCAC scale is a multidimensional measure of varying aspects of reproductive concerns, and results suggest that the scale may be best represented as a profile of subscale scores. The subscale scores would be useful for tailoring recommendations and interventions to more effectively address the diverse reproductive concerns of female reproductive‐aged survivors.
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