Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. The multikinase inhibitor sorafenib only demonstrated marginal improvement in overall survival for ...advanced disease prompted the search for alternative treatment options. Human mesenchymal stem cells (MSCs) have the ability to home to tumor cells. However, its functional roles on the tumor microenvironment remain controversial. Herein, we showed that conditioned media derived from human fetal MSC (CM-hfMSCs) expressed high level of the insulin growth factor binding proteins IGFBPs and can sequester free insulin-like growth factors (IGFs) to inhibit HCC cell proliferation. The inhibitory effect of IGFBPs on IGF signaling was further evident from the reduction of activated IGF-1R and PI3K/Akt, leading eventually to the induction of cell cycle arrest. We also demonstrated that CM-hfMSCs could enhance the therapeutic efficacy of sorafenib and sunitinib. To the best of our knowledge, this is the first report to show that CM-hfMSCs has a tumor-specific, antiproliferative effect that is not observed with normal human hepatocyte cells and patient-derived matched normal tissues. Our results thus suggest that CM-hfMSCs can provide a useful tool to design alternative/adjuvant treatment strategies for HCC, especially in related function to potentiate the effects of chemotherapeutic drugs.
Inherited germline mutations in the breast cancer gene 1 (BRCA1) or BRCA2 genes (herein BRCA1/2) greatly increase the risk of breast and ovarian cancer, presumably by elevating somatic mutational ...errors as a consequence of deficient DNA repair. However, this has never been directly demonstrated by a comprehensive analysis of the somatic mutational landscape of primary, noncancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1/2 germline mutations. Here, we used an accurate, single-cell whole-genome sequencing approach to first show that telomerized primary mammary epithelial cells heterozygous for a highly penetrant BRCA1 variant displayed a robustly elevated mutation frequency as compared with their isogenic control cells. We then demonstrated a small but statistically significant increase in mutation frequency in mammary epithelial cells isolated from the breast of BRCA1/2 mutation carriers as compared with those obtained from age-matched controls with no genetically increased risk for breast cancer.
The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B ...lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self-ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2-dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.
Global assessment of the spatiotemporal variability in terrestrial total water storage anomalies (TWSA) in response to hydrologic extremes is critical for water resources management. Using TWSA ...derived from the gravity recovery and climate experiment (GRACE) satellites, this study systematically assessed the skill of the TWSA-climatology (TC) approach and breakpoint (BP) detection method for identifying large-scale hydrologic extremes. The TC approach calculates standardized anomalies by using the mean and standard deviation of the GRACE TWSA corresponding to each month. In the BP detection method, the empirical mode decomposition (EMD) is first applied to identify the mean return period of TWSA extremes, and then a statistical procedure is used to identify the actual occurrence times of abrupt changes (i.e., BPs) in TWSA. Both detection methods were demonstrated on basin-averaged TWSA time series for the world’s 35 largest river basins. A nonlinear event coincidence analysis measure was applied to cross-examine abrupt changes detected by these methods with those detected by the Standardized Precipitation Index (SPI). Results show that our EMD-assisted BP procedure is a promising tool for identifying hydrologic extremes using GRACE TWSA data. Abrupt changes detected by the BP method coincide well with those of the SPI anomalies and with documented hydrologic extreme events. Event timings obtained by the TC method were ambiguous for a number of river basins studied, probably because the GRACE data length is too short to derive long-term climatology at this time. The BP approach demonstrates a robust wet-dry anomaly detection capability, which will be important for applications with the upcoming GRACE Follow-On mission.
► An inversion algorithm is developed for detecting leakage at geologic CO2 sequestration sites. ► The algorithm is based on inversion of observed pressure anomalies. ► The algorithm is successfully ...demonstrated for detecting both leakage locations and rates. ► The tool can be readily incorporated into existing CO2 risk management frameworks.
Leakage from abandoned wells and geologic faults represents one of the greatest risks to the integrity of geologic CO2 sequestration sites. The ability to detect leakage in a timely manner is, therefore, crucial for mitigating the potential adverse impacts of leakage to the public and environment. We present an inversion approach for recovering both leakage locations and rates by using observed pressure anomaly data. The approach is based on formulation of a linear system of equations using the unit-step response method, which is applicable to both analytical and numerical models. Because the resulting system is often ill conditioned, we investigate the efficacy of regularization methods for stabilizing the solutions. Further, when prior information is insufficient to restrict the number of search locations, a global optimization algorithm is used to solve the challenging problem of joint location and leakage history inversion. The performance of several linear inversion solvers is compared while considering effects such as measurement error and spatial heterogeneity. The results are promising and suggest that our pressure-anomaly-based leakage detection algorithm can be used to identify leaky wells in practice. It can be deployed as an integrated component of CO2 risk management frameworks.
The Gravity Recovery and Climate Experiment (GRACE) satellites provide a powerful tool for monitoring sediment mass change. However, signal leakage from nearby groundwater storage depletion in the ...North China Plain limits the potential capacity of GRACE to estimate sediment input from the Yellow River flows into the Bohai Sea. In the present work, we developed an improved approach based on forward modeling to reduce signal leakage from GRACE data and combined it with satellite altimetry to recover sediment load changes from 2003 to 2013 to the Bohai Sea. The total sediment input averaged 1.7 ± 0.8 Gt/yr, which agrees well with the estimate based on in-situ sediment data measured from the sediment cores (1.1 Gt/yr). Our method is also capable to describe sediment seasonal variations, with higher inputs in winter and spring, which confirm the output simulated by the sediment transportation model. We make presently tentative connections of seasonal variations to sediment resuspension driven by climatic monsoons contributed rough seas: although sediment load in rivers peaks in summer, low water discharge of the Yellow River leads to most of the sediment being deposited in a narrow area near the river mouth and not transported into the Bohai Sea; in winter and spring, huge waves provide favorable conditions for resuspension resulting in large amounts of sediment near the estuary being transported to the ocean along with northward waves. Moreover, our results indicate coastal erosion is also a nonnegligible resource of the sediment in the Bohai Sea. Comparing to the traditional approach, our study provides a new technological way to derive sediment in the Bohai Sea, which is capable of providing continuous measurements with improved timeliness at a lower cost.
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•An improved forward modeling method was developed to reduce GRACE signal leakage.•Sediment in the Bohai Sea was derived by combining GRACE and satellite altimetry.•Sediment shows seasonal variations, with higher inputs in winter and spring.•Sediment seasonal variations is caused by climatic monsoons contributed rough seas.
Regulatory T (Treg) cells represent a specialized lineage of suppressive CD4+ T cells whose functionality is critically dependent on their ability to migrate to and dwell in the proximity of cells ...they control. Here we show that continuous expression of the chemokine receptor CXCR4 in Treg cells is required for their ability to accumulate in the bone marrow (BM). Induced CXCR4 ablation in Treg cells led to their rapid depletion and consequent increase in mature B cells, foremost the B-1 subset, observed exclusively in the BM without detectable changes in plasma cells or hematopoietic stem cells or any signs of systemic or local immune activation elsewhere. Dysregulation of BM B-1 B cells was associated with a highly specific increase in IgM autoantibodies and total serum IgM levels. Thus, Treg cells control autoreactive B-1 B cells in a CXCR4-dependent manner. These findings have significant implications for understanding the regulation of B cell autoreactivity and malignancies.
Natural killer (NK) cells function in the recognition and destruction of host cells infected with pathogens. Many regulatory mechanisms govern the potent responses of NK cells, both at the cellular ...and molecular level. Ablation of microRNA (miRNA) processing enzymes demonstrated that miRNAs play critical roles in NK cell differentiation and function; however, the role of individual miRNAs requires further investigation. Using mice containing a targeted deletion of microRNA-155 (miR-155), we observed defects in NK cell maintenance and maturation at steady state, as well as in homeostatic proliferation in lymphopenic mice. In addition, we discovered that miR-155 is up-regulated in activated NK cells during mouse cytomegalovirus (MCMV) infection in response to signals from the proinflammatory cytokines IL-12 and IL-18 and through signal transducer and activator of transcription 4 (STAT4) signaling. Although miR-155 was found to be dispensable for cytotoxicity and cytokine production when triggered through activating receptors, NK cells lacking miR-155 exhibited severely impaired effector and memory cell numbers in both lymphoid and nonlymphoid tissues after MCMV infection. We demonstrate that miR-155 differentially targets Noxa and suppressor of cytokine signaling 1 (SOCS1) in NK cells at distinct stages of homeostasis and activation. NK cells constitutively expressing Noxa and SOCS1 exhibit profound defects in expansion during the response to MCMV infection, suggesting that their regulation by miR-155 promotes antiviral immunity.
This study proposes a hydrological drought index, the standardized wetness index (SWI), by combining the structure of the Standardized Precipitation‐Evapotranspiration Index and ...actual‐evaporation‐based residual water‐energy ratio, in which actual evaporation is estimated using the Budyko hypothesis. The SWI requires three parameters—precipitation, potential evaporation, and parameter
n of a Budyko‐type formula. Based on different types of
n (fixed or dynamic), SWI can be used to estimate the dryness/wetness resulting from climate change (variability) solely, and from the joint effects of climate and land surface change (variability). Performance of SWI is evaluated using historical droughts and by comparing to the self‐calibrated Palmer Drought Severity Index. Results show that SWI effectively captures global droughts. Furthermore, a case study in two catchments with significant land surface modification indicates that the joint effects of climate and land surface have greater impacts on dryness/wetness in the water‐limited Wuding catchment than in the energy‐limited Poyang catchment.
Key Points
Newly developed drought index SWI considers the joint effects of climate and land surface change (variability)
SWI has potential to evaluate the impacts of climate and land surface changes (variability) on dryness/wetness
Land surface change has larger (less) impacts on drought conditions in water‐limited Wuding (energy‐limited Poyang) catchment
We present the ionized gas properties of infrared (IR)-bright dust-obscured galaxies (DOGs) that show an extreme optical/IR color, , selected with the Sloan Digital Sky Survey (SDSS) and Wide-field ...Infrared Survey Explorer (WISE). For 36 IR-bright DOGs that show O iiiλ5007 emission in the SDSS spectra, we performed a detailed spectral analysis to investigate their ionized gas properties. In particular, we measured the velocity offset (the velocity with respect to the systemic velocity measured from the stellar absorption lines) and the velocity dispersion of the O iii line. We found that the derived velocity offset and dispersion of most IR-bright DOGs are larger than those of Seyfert 2 galaxies (Sy2s) at , meaning that the IR-bright DOGs show relatively strong outflows compared to Sy2s. This can be explained by the difference in IR luminosity contributed from active galactic nuclei, (AGN), because we found that (i) (AGN) correlates with the velocity offset and dispersion of O iii and (ii) our IR-bright DOG sample has larger (AGN) than Sy2s. Nevertheless, the fact that about 75% IR-bright DOGs have a large (>300 km s−1) velocity dispersion, which is a larger fraction compared to other AGN populations, suggests that IR-bright DOGs are good laboratories to investigate AGN feedback. The velocity offset and dispersion of O iii and Ne iiiλ3869 are larger than those of O iiλ3727, which indicates that the highly ionized gas tends to show stronger outflows.
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