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"Hu, H."
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Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance
Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Journal Article
Temperature Changes in Central Asia from 1979 to 2011 Based on Multiple Datasets
The arid and semiarid region in central Asia is sensitive and vulnerable to climate variations. However, the sparse and highly unevenly distributed meteorological stations in the region provide limited data for understanding of the region’s climate variations. In this study, the near-surface air temperature change in central Asia from 1979 to 2011 was examined using observations from 81 meteorological stations, three local observation validated reanalysis datasets of relatively high spatial resolutions, and the Climate Research Unit (CRU) dataset. Major results suggested that the three reanalysis datasets match well with most of the local climate records, especially in the low-lying plain areas. The consensus of the multiple datasets showed significant regional surface air temperature increases of 0.36°–0.42°C decade−1in the past 33 years. No significant contributions from declining irrigation and urbanization to temperature change were found. The rate is larger in recent years than in the early years in the study period. Additionally, unlike in many regions in the world, the temperature in winter showed no increase in central Asia in the last three decades, a noticeable departure from the global trend in the twentieth century. The largest increase in surface temperature was occurring in the spring season. Analyses further showed a warming center in the middle of the central Asian states and weakened temperature variability along the northwest–southeast temperature gradient from the northern Kazakhstan to southern Xinjiang. The reanalysis datasets also showed significant negative correlations between temperature increase rate and elevation in this complex terrain region.
Journal Article
Diagnostic calibration of a hydrological model in a mountain area by hydrograph partitioning
Hydrological modeling can exploit informative signatures extracted from long time sequences of observed streamflow for parameter calibration and model diagnosis. In this study we explore the diagnostic potential of hydrograph partitioning for model calibration in mountain areas, where meltwater from snow and glaciers is an important source for river runoff (in addition to rainwater). We propose an index-based method to partition the hydrograph according to dominant runoff water sources, and a diagnostic approach to calibrate a mountain hydrological model. First, by accounting for the seasonal variability of precipitation and the altitudinal variability of temperature and snow/glacier coverage, we develop a set of indices to indicate the daily status of runoff generation from each type of water source (i.e., glacier meltwater, snow meltwater, rainwater, and groundwater). Second, these indices are used to partition a hydrograph into four parts associated with four different combinations of dominant water sources (i.e., groundwater, groundwater + snow meltwater, groundwater + snow meltwater + glacier meltwater, and groundwater + snow meltwater + glacier meltwater + rainwater). Third, the hydrological model parameters are grouped by the associated runoff sources, and each group is calibrated to match the corresponding hydrograph partition in a stepwise and iterative manner. Similar to use of the regime curve to diagnose seasonality of streamflow, the hydrograph partitioning curve based on a dominant runoff water source (more briefly called the partitioning curve, not necessarily continuous) can serve as a diagnostic signature that helps relate model performance to model components. The proposed methods are demonstrated via application of a semi-distributed hydrological model (THREW, Tsinghua Representative Elementary Watershed) to the Tailan River basin (TRB) (1324 km2) in the Tianshan Mountains of China. Results show that the proposed calibration approach performed reasonably well. Cross-validation and comparison to an automatic calibration method indicated its robustness.
Journal Article
Soil moisture controls on patterns of grass green-up in Inner Mongolia: an index based approach
Water availability is one of the most important environmental controls on vegetation phenology, especially in semi-arid regions. It is often represented in terms of soil moisture in small-scale studies, whereas it tends to be represented by precipitation in large-scale (e.g., regional) studies. Clearly, soil moisture is the more appropriate indicator for root water uptake and vegetation growth/phenology. Its potential advantage and applicability needs to be demonstrated at regional scales. The paper presents a data-based regional study of the effectiveness of novel water and temperature-based indices to predict spring vegetation green-up dates based on the Normalized Difference Vegetation Index (NDVI) observations in the grasslands of Inner Mongolia, China. The macro-scale hydrological model, VIC (Variable Infiltration Capacity), is employed to generate a soil moisture database across the region. In addition to a standard index based on temperature, two potential hydrology-based indices for prediction of spring onset dates are defined, based on the simulated soil moisture data as well as on observed precipitation data. Results indicate that the correspondence between the NDVI-derived green-up onset date and the soil-moisture-derived potential onset date exhibits a significantly better correlation as a function of increasing aridity compared to that based on precipitation. In this way the soil-moisture-based index is demonstrated to be superior to the precipitation-based index in terms of capturing grassland spring phenology. The results also showed that both of the hydrological (water-based) indices were superior to the thermal (temperature-based) index in determining the patterns of grass green-up in the Inner Mongolia region, indicating water availability to be the dominant control on average. The understanding about the relative controls on grassland phenology and the effectiveness of alternative indices to capture these controls are important for future studies of vegetation phenology change under climate change.
Journal Article
On the importance of interplanetary magnetic field ∣By∣ on polar cap patch formation
A number of poleward moving events were observed between 1130 and 1300 UT on 11 February 2004, during periods of southward interplanetary magnetic field (IMF), while the steerable antenna of the European Incoherent Scatter (EISCAT) Svalbard radar (ESR) and the Tromsø VHF radar pointed nearly northward at low elevation. In this interval, simultaneous SuperDARN CUTLASS Finland radar measurements showed poleward moving radar aurora forms (PMRAFs) which appeared very similar to the density enhancements observed by the ESR northward pointing antenna. These events appeared quasiperiodically with a period of about 10 min. Comparing the observations from the above three radars, it is inferred that there is an almost one‐to‐one correspondence between the poleward moving plasma concentration enhancements (PMPCEs) observed by the ESR and the VHF radar and the PMRAFs measured by the CUTLASS Finland radar. These observations are consistent with the interpretation that the polar cap patch material was generated by photoionization at subauroral latitudes and that the plasma was structured by bursts of magnetopause reconnection giving access to the polar cap. There is clear evidence that plasma structuring into patches was dependent on the variability in IMF ∣By∣. The duration of these events implies that the average evolution time of the newly opened flux tubes from the subauroral region to the polar cap was about 33 min. Key Points The observations reveal the formation of polar cap patches The formation of polar cap patch was dependent on the variability in IMF By Implied open flux tube evolves ∼33 min from subauroral region to the polar cap
Journal Article
Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels
The extracellular matrix (ECM) is a complex assembly of structural proteins that provides physical support and biochemical signaling to cells in tissues. The mechanical properties of the ECM have been found to play a key role in regulating cell behaviors such as differentiation and malignancy. Gels formed from ECM protein biopolymers such as collagen or fibrin are commonly used for 3D cell culture models of tissue. One of the most striking features of these gels is that they exhibit nonlinear elasticity, undergoing strain stiffening. However, these gels are also viscoelastic and exhibit stress relaxation, with the resistance of the gel to a deformation relaxing over time. Recent studies have suggested that cells sense and respond to both nonlinear elasticity and viscoelasticity of ECM, yet little is known about the connection between nonlinear elasticity and viscoelasticity. Here, we report that, as strain is increased, not only do biopolymer gels stiffen but they also exhibit faster stress relaxation, reducing the timescale over which elastic energy is dissipated. This effect is not universal to all biological gels and is mediated through weak cross-links. Mechanistically, computational modeling and atomic force microscopy (AFM) indicate that strain-enhanced stress relaxation of collagen gels arises from force-dependent unbinding of weak bonds between collagen fibers. The broader effect of strain-enhanced stress relaxation is to rapidly diminish strain stiffening over time. These results reveal the interplay between nonlinear elasticity and viscoelasticity in collagen gels, and highlight the complexity of the ECM mechanics that are likely sensed through cellular mechanotransduction.
Journal Article
Aptazyme-embedded guide RNAs enable ligand-responsive genome editing and transcriptional activation
Programmable sequence-specific genome editing agents such as CRISPR-Cas9 have greatly advanced our ability to manipulate the human genome. Although canonical forms of genome-editing agents and programmable transcriptional regulators are constitutively active, precise temporal and spatial control over genome editing and transcriptional regulation activities would enable the more selective and potentially safer use of these powerful technologies. Here, by incorporating ligand-responsive self-cleaving catalytic RNAs (aptazymes) into guide RNAs, we developed a set of aptazyme-embedded guide RNAs that enable small molecule-controlled nuclease-mediated genome editing and small molecule-controlled base editing, as well as small molecule-dependent transcriptional activation in mammalian cells.
CRISPR-Cas9 is a powerful technique for manipulating the human genome, however temporal and spatial control of activity would facilitate safer, more selective use. Here the authors incorporate aptazymes into guide RNAs to allow small molecule activation of CRISPR-Cas9.
Journal Article
Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents
CRISPR–Cas9 genome editing is used to correct a dominant-negative mutation in a mouse model of inherited deafness, resulting in improvements in cochlear function and hearing.
Hindering heritable hearing loss
Nearly half of all deafness cases arise from genetic factors, yet there are limited treatment options available for inherited hearing loss. David Liu and colleagues develop a genome-editing approach to target a dominantly inherited form of deafness. In a mouse model of human deafness, CRISPR–Cas9 editing can disrupt the mutant allele and reduce hearing loss. The results support the potential utility of protein–RNA complex delivery in post-mitotic cells as a gene-editing strategy for some autosomal-dominant diseases.
Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited
1
,
2
,
3
,
4
,
5
. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated
in vivo
delivery of Cas9–guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both
in vitro
and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the
Tmc1
(transmembrane channel-like gene family 1) Beethoven (
Bth
) mouse model, even though the mutant
Tmc1
Bth
allele differs from the wild-type allele at only a single base pair. Injection of Cas9–guide RNA–lipid complexes targeting the
Tmc1
Bth
allele into the cochlea of neonatal
Tmc1
Bth
/+
mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected
Tmc1
Bth
/+
mice. These findings suggest that protein–RNA complex delivery of target gene-disrupting agents
in vivo
is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.
Journal Article
Noise as Information for Illiquidity
We propose a market-wide liquidity measure by exploiting the connection between the amount of arbitrage capital in the market and observed \"noise\" in U.S. Treasury bonds—the shortage of arbitrage capital allows yields to deviate more freely from the curve, resulting in more noise in prices. Our noise measure captures episodes of liquidity crises of different origins across the financial market, providing information beyond existing liquidity proxies. Moreover, as a priced risk factor, it helps to explain cross-sectional returns on hedge funds and currency carry trades, both known to be sensitive to the general liquidity conditions of the market.
Journal Article