Intranational synergies and trade-offs reveal common and differentiated priorities of sustainable development goals in China.

Accelerating efforts for the Sustainable Development Goals requires understanding their synergies and trade-offs at the national and sub-national levels, which will help identify the key hurdles and opportunities to prioritize them in an indivisible manner for a country. Here, we present the importance of the 17 goals through synergy and trade-off networks. Our results reveal that 19 provinces show the highest trade-offs in SDG13 (Combating Climate Change) or SDG5 (Gender Equality) consistent with the national level, with other 12 provinces varying. 24 provinces show the highest synergies in SDG1 (No Poverty) or SDG6 (Clean Water and Sanitation) consistent with the national level, with the remaining 7 provinces varying. These common but differentiated SDG priorities reflect that to ensure a coordinated national response, China should pay more attention to the provincial situation, so that provincial governments can formulate more targeted policies in line with their own priorities towards accelerating sustainable development.

Weakening warming on spring freeze-thaw cycle caused greening Earth's third pole.

The Tibetan Plateau, recognized as Earth's third pole and among the most responsive regions to climate shifts, profoundly influences regional and even global hydrological processes. Here, we discerned a significant weakening in the influence of temperature on the initiation of surface freeze-thaw cycle (the Start of Thawing, SOT), which can be ascribed to a multitude of climatic variables, with radiation emerging as the most pivotal factor. Additionally, we showed that the diminishing impact of warming on SOT yields amplified soil moisture within the root zone. This, in turn, fosters a greening third pole with increased leaf area index and solar-induced chlorophyll fluorescence. We further showed that current Earth system models failed to reproduce the linkage between weakened sensitivity and productivity under various shared socioeconomic pathways. Our findings highlight the dynamic shifts characterizing the influence of climate warming on spring freeze-thaw process and underscore the profound ecological implications of these changes in the context of future climate scenarios.

Critical role of water conditions in the responses of autumn phenology of marsh wetlands to climate change on the Tibetan Plateau.

The Tibetan Plateau, housing 20% of China's wetlands, plays a vital role in the regional carbon cycle. Examining the phenological dynamics of wetland vegetation in response to climate change is crucial for understanding its impact on the ecosystem. Despite this importance, the specific effects of climate change on wetland vegetation phenology in this region remain uncertain. In this study, we investigated the influence of climate change on the end of the growing season (EOS) of marsh wetland vegetation across the Tibetan Plateau, utilizing satellite-derived Normalized Difference Vegetation Index (NDVI) data and observational climate data. We observed that the regionally averaged EOS of marsh vegetation across the Tibetan Plateau was significantly (p < .05) delayed by 4.10 days/decade from 2001 to 2020. Warming preseason temperatures were found to be the primary driver behind the delay in the EOS of marsh vegetation, whereas preseason cumulative precipitation showed no significant impact. Interestingly, the responses of EOS to climate change varied spatially across the plateau, indicating a regulatory role for hydrological conditions in marsh phenology. In the humid and cold central regions, preseason daytime warming significantly delayed the EOS. However, areas with lower soil moisture exhibited a weaker or reversed delay effect, suggesting complex interplays between temperature, soil moisture, and EOS. Notably, in the arid southwestern regions of the plateau, increased preseason rainfall directly delayed the EOS, while higher daytime temperatures advanced it. Our results emphasize the critical role of hydrological conditions, specifically soil moisture, in shaping marsh EOS responses in different regions. Our findings underscore the need to incorporate hydrological factors into terrestrial ecosystem models, particularly in cold and dry regions, for accurate predictions of marsh vegetation phenological responses to climate change. This understanding is vital for informed conservation and management strategies in the face of current and future climate challenges.

Recent advances of silk fibroin materials: From molecular modification and matrix enhancement to possible encapsulation-related functional food applications.

Silk fibroin materials are emergingly explored for food applications due to their inherent properties including safe oral consumption, biocompatibility, gelatinization, antioxidant performance, and mechanical properties. However, silk fibroin possesses drawbacks like brittleness owing to its inherent specific composition and structure, which limit their applications in this field. This review discusses current progress about molecular modification methods on silk fibroin such as extraction, blending, self-assembly, enzymatic catalysis, etc., to address these limitations and improve their physical/chemical properties. It also summarizes matrix enhancement strategies including freeze drying, spray drying, electrospinning/electrospraying, microfluidic spinning/wheel spinning, desolvation and supercritical fluid, to generate nano-, submicron-, micron-, or bulk-scale materials. It finally highlights the food applications of silk fibroin materials, including nutraceutical improvement, emulsions, enzyme immobilization and 3D/4D printing. This review also provides insights on potential opportunities (like safe modification, toxicity risk evaluation, and digestion conditions) and possibilities (like digital additive manufacturing) in functional food industry.

Optimizing the detection of emerging infections using mobility-based spatial sampling.

Background: Timely and precise detection of emerging infections is crucial for effective outbreak management and disease control. Human mobility significantly influences infection risks and transmission dynamics, and spatial sampling is a valuable tool for pinpointing potential infections in specific areas. This study explored spatial sampling methods, informed by various mobility patterns, to optimize the allocation of testing resources for detecting emerging infections. Methods: Mobility patterns, derived from clustering point-of-interest data and travel data, were integrated into four spatial sampling approaches to detect emerging infections at the community level. To evaluate the effectiveness of the proposed mobility-based spatial sampling, we conducted analyses using actual and simulated outbreaks under different scenarios of transmissibility, intervention timing, and population density in cities. Results: By leveraging inter-community movement data and initial case locations, the proposed case flow intensity (CFI) and case transmission intensity (CTI)-informed sampling approaches could considerably reduce the number of tests required for both actual and simulated outbreaks. Nonetheless, the prompt use of CFI and CTI within communities is imperative for effective detection, particularly for highly contagious infections in densely populated areas. Conclusions: The mobility-based spatial sampling approach can substantially improve the efficiency of community-level testing for detecting emerging infections. It achieves this by reducing the number of individuals screened while maintaining a high accuracy rate of infection identification. It represents a cost-effective solution to optimize the deployment of testing resources, when necessary, to contain emerging infectious diseases in diverse settings.

Analysis of the risk factors of radiation pneumonitis in patients after radiotherapy for esophageal squamous cell carcinoma.

Objective: To predict the risk factors of radiation pneumonitis (RP) in patients with esophageal squamous cell carcinoma (ESCC) who received radiotherapy. Methods: From January 2015 to October 2021, 477 ESCC patients were enrolled and were assessed retrospectively. All these patients received radiotherapy for primary lesions or mediastinal metastatic lymph nodes. Clinical efficacy and adverse events (AEs) were observed. Univariate analysis identified clinical and dosimetric factors associated with the development of RP, and multivariate logistic regression analysis identified independent potential risk factors associated with the development of RP. Nomograms were constructed to predict RP based on the results of multivariate logistic regression analysis. Results: Among the 477 ESCC patients, the incidence of RP was 22.2%, and the incidence of grade 4 or higher RP was 1.5%. Univariate analysis indicated that chronic obstructive pulmonary disease (COPD), pulmonary infection, leucopenia, PTV volume, V5, V20, V30 and MLD affected the occurrence of RP. The multivariate logistic regression analysis indicated that COPD (OR:1.821, 95%CI:1.111-2.985; P=0.017), pulmonary infection (OR:2.528, 95%CI:1.530-4.177; P<0.001), higher V20 (OR: 1.129, 95% CI:1.006-1.266; P=0.029) were significant independent predictors of RP in ESCC patients. COPD, pulmonary infection, V20 have been integrated for the RP nomogram. The rate of RP was significantly reduced in the V20<21.45% group. Further analysis indicated that the old age, diabetes, higher V20, and higher MLD were risk factors for grade 4 or higher RP. The area under the curve (AUC) value for V20 was 0.73 (95% CI, 0.567-0.893, P < 0.05). Conclusion: We have determined the risk factors of RP and grade 4 or higher RP in ESCC patients after radiotherapy. MLD, V20, COPD were independent factors for RP. It was necessary to take measures to reduce or avoid the occurrence of RP for patients with these risk factors at the early stage.

Hydrogel-based molecular tension fluorescence microscopy for investigating receptor-mediated rigidity sensing.

Extracellular matrix (ECM) rigidity serves as a crucial mechanical cue impacting diverse biological processes. However, understanding the molecular mechanisms of rigidity sensing has been limited by the spatial resolution and force sensitivity of current cellular force measurement techniques. Here we developed a method to functionalize DNA tension probes on soft hydrogel surfaces in a controllable and reliable manner, enabling molecular tension fluorescence microscopy for rigidity sensing studies. Our findings showed that fibroblasts respond to substrate rigidity by recruiting more force-bearing integrins and modulating integrin sampling frequency of the ECM, rather than simply overloading the existing integrin-ligand bonds, to promote focal adhesion maturation. We also demonstrated that ECM rigidity positively regulates the pN force of T cell receptor-ligand bond and T cell receptor mechanical sampling frequency, promoting T cell activation. Thus, hydrogel-based molecular tension fluorescence microscopy implemented on a standard confocal microscope provides a simple and effective means to explore detailed molecular force information for rigidity-dependent biological processes.

Stabilization of capsanthin in physically-connected hydrogels: Rheology property, self-recovering performance and syringe/screw-3D printing.

This work presented a facile way of stabilizing capsanthin by physically-connected soft hydrogels via utilizing specially-structured polysaccharides, and investigated rheological properties, self-recovering mechanism and 3D printability. The functionalized hydrogels demonstrated excellent color quality including redness, yellowness index and hue with great storage stability and visual perception. The soft hydrogels fabricated with properly sequenced polyglyceryl fatty acid esters, ß-cyclodextrin, chitosan, and low-content capsanthin possessed outstanding extrudability, appropriate yield stress, reasonable mechanical strength, rational elasticity and structure sustainability. Furthermore, the self-recovering properties based on hydrogen bonds, host-guest interactions and electrostatic interactions were revealed and verified by structural, zeta potential, micro-morphological, zeta potential, thixotropic, creep-recovery, and macroscopic/microscopic characterizations. Along with excellent antioxidant performance, the subsequent 3D printing onto bread with complex models elucidated the high geometry accuracy and great sensory characters. The sequenced physically-connected hydrogels incorporated with capsanthin can provide new insights on stabilizing hydrophobic biomaterials and developing the 3D printed exquisite, innovative food.

Global future population exposure to heatwaves.

The increasing exposure to extreme heatwaves in urban areas from both climate change and the urban heat island (UHI) effect poses multiple threats and challenges to human society. Despite a growing number of studies focusing on extreme exposure, research advances are still limited in some aspects such as oversimplification of human exposure to heatwaves and neglect of perceived temperature as well as actual body comfort, resulting in unreliable and unrealistic estimates of future results. In addition, little research has performed comprehensive and fine-resolution global analyses in future scenarios. In this study, we present the first global fine-resolution projection of future changing urban population exposure to heatwaves by 2100 under four shared socioeconomic pathways (SSPs) considering urban expansion at global, regional, and national scales. Overall, global urban population exposure to heatwaves is rising under the four SSPs. Temperate and tropical zones predictably have the greatest exposure among all climate zones. Coastal cities are projected to have the greatest exposure, followed closely by cities at low altitudes. Middle-income countries have the lowest exposure and the lowest inequality of exposure among countries. Individual climate effects contributed the most (approximately 46.4%) to future changes in exposure, followed by the interactive effect between climate and urbanization (approximately 18.5%). Our results indicate that more attention needs to be paid to policy improvements and sustainable development planning of global coastal cities and some low-altitude cities, especially in low- and high-income countries. Meanwhile, this study also highlights the impact of continued future urban expansion on population exposure to heatwaves.

Molecular Force Imaging Reveals That Integrin-Dependent Mechanical Checkpoint Regulates Fcγ-Receptor-Mediated Phagocytosis in Macrophages.

Macrophages are a type of immune cell that helps eliminate pathogens and diseased cells. Recent research has shown that macrophages can sense mechanical cues from potential targets to perform effective phagocytosis, but the mechanisms behind it remain unclear. In this study, we used DNA-based tension probes to study the role of integrin-mediated forces in FcγR-mediated phagocytosis. The results showed that when the phagocytic receptor FcγR is activated, the force-bearing integrins create a "mechanical barrier" that physically excludes the phosphatase CD45 and facilitates phagocytosis. However, if the integrin-mediated forces are physically restricted at lower levels or if the macrophage is on a soft matrix, CD45 exclusion is significantly reduced. Moreover, CD47-SIRPα "don't eat me" signaling can reduce CD45 segregation by inhibiting the mechanical stability of the integrin barrier. These findings demonstrate how macrophages use molecular forces to identify physical properties and combine them with biochemical signals from phagocytic receptors to guide phagocytosis.

Future population exposure to heatwaves in 83 global megacities.

Global warming leads to more frequent and intense heatwaves, putting urban populations at greater risk. Previous related studies considered only surface air temperature or one or two Shared Socioeconomic Pathways (SSPs) and were limited to specific regions. Moreover, no research focused on heatwave exposure in highly-populated global megacities facing severe threats. This study is the first to project future population exposure to heatwaves in 83 global megacities by 2100 using fine-resolution data, suitable indices reflecting human comfort in heatwaves by incorporating temperature and humidity, and a future population exposure projection and analysis framework. The results show that (1) the global frequency of extreme heatwave events and average change rate in each megacity sequentially increase from SSP1-2.6 to SSP5-8.5, and the change rate is generally larger in megacities in the Southern Hemisphere; (2) the increases in heatwave exposure are greatest under SSP370, and the change rates are generally larger for megacities in Southern Asia; (3) there is a high degree of inequality (Gini of 0.6 to 0.63) in future heatwave exposure globally, with the highest inequality under SSP5-8.5 and the lowest under SSP3-7.0; (4) the average exposure, increase rate, and change are highest in low-income megacities and lowest in high-income megacities. The distribution of exposure is the most balanced in middle-income megacities and the least balanced in high-income megacities; and (5) population growth contributes more to the change in exposure than total warming in high-income megacities under SSP1-2.6, and total urban warming contributes much more than population growth in all other cases. Every effort should be made to avoid the SSP3-7.0 scenario and pursue sustainable and rational urban economic development. Mumbai, Manila, Kolkata, and Jakarta warrant particular attention due to their rapid exposure growth. Additionally, policymakers and urban planners must focus on improving sustainable development planning for megacities in southern Asia and low-income megacities.

New prognostic system specific for epidermal growth factor receptor-mutated lung cancer brain metastasis.

Introduction: Brain metastases (BM) from lung cancer are heterogeneous, and accurate prognosis is required for effective treatment strategies. This study aimed to identify prognostic factors and develop a prognostic system exclusively for epidermal growth factor receptor (EGFR)-mutated lung cancer BM. Methods: In total, 173 patients with EGFR-mutated lung cancer from two hospitals who developed BM and received tyrosine kinase inhibitor (TKI) and brain radiation therapy (RT) were included. Univariate and multivariate analyses were performed to identify significant EGFR-mutated BM prognostic factors to construct a new EGFR recursive partitioning analysis (RPA) prognostic index. The predictive discrimination of five prognostic scoring systems including RPA, diagnosis-specific prognostic factors indexes (DS-GPA), basic score for brain metastases (BS-BM), lung cancer using molecular markers (lung-mol GPA) and EGFR-RPA were analyzed using log-rank test, concordance index (C-index), and receiver operating characteristic curve (ROC). The potential predictive factors in the multivariable analysis to construct a prognostic index included Karnofsky performance status, BM at initial lung cancer diagnosis, BM progression after TKI, EGFR mutation type, uncontrolled primary tumors, and number of BM. Results and discussion: In the log-rank test, indices of RPA, DS-GPA, lung-mol GPA, BS-BM, and EGFR-RPA were all significant predictors of overall survival (OS) (p ≤ 0.05). The C-indices of each prognostic score were 0.603, 0.569, 0.613, 0.595, and 0.671, respectively; The area under the curve (AUC) values predicting 1-year OS were 0.565 (p=0.215), 0.572 (p=0.174), 0.641 (p=0.007), 0.585 (p=0.106), and 0.781 (p=0.000), respectively. Furthermore, EGFR-RPA performed better in terms of calibration than other prognostic indices.BM progression after TKI and EGFR mutation type were specific prognostic factors for EGFR-mutated lung cancer BM. EGFR-RPA was more precise than other models, and useful for personal treatment.

Increasing temperature regulates the advance of peak photosynthesis timing in the boreal ecosystem.

The shift in vegetation phenology is an essential indicator of global climate change. Numerous researches based on reflectance-based vegetation index data have explored the changes in the start (SOS) and end (EOS) of vegetation life events at long time scales, while a huge discrepancy existed between the phenological metrics of vegetation structure and function. The peak photosynthesis timing (PPT), which is crucial in regulating terrestrial ecosystem carbon balance, has not received much attention. Using two global reconstructed solar-induced chlorophyll fluorescence data (CSIF and GOSIF) directly associated with vegetation photosynthesis, the spatio-temporal dynamics in PPT as well as the key environmental controls across the boreal ecosystem during 2001-2019 were systematically explored. Multi-year mean pattern showed that PPT mainly appeared in the first half of July. Compared to the northern Eurasia, later PPT appeared in the northern North America continent for about 4-5 days. Meanwhile, spatial trend in PPT exhibited an advanced trend during the last two decades. Especially, shrubland and grassland were obvious among all biomes. Spatial partial correlation analysis revealed that preseason temperature was the dominant environmental driver of PPT trends, occupying 81.32% and 78.04% of the total pixels of PPTCSIF and PPTGOSIF, respectively. Attribution analysis by ridge regression again emphasized the largest contribution of temperature to PPT dynamics in the boreal ecosystem by 52.22% (PPTCSIF) and 46.59% (PPTGOSIF), followed by radiation (PPTCSIF: 24.44%; PPTGOSIF: 28.66%) and precipitation (PPTCSIF: 23.34%; PPTGOSIF: 24.75%). These results have significant implications for deepening our understanding between vegetation photosynthetic phenology and carbon cycling with respect to future climate change in the boreal ecosystem.

The start of frozen dates over northern permafrost regions with the changing climate.

The soil freeze-thaw cycle in the permafrost regions has a significant impact on regional surface energy and water balance. Although increasing efforts have been made to understand the responses of spring thawing to climate change, the mechanisms controlling the global interannual variability of the start date of permafrost frozen (SOF) remain unclear. Using long-term SOF from the combinations of multiple satellite microwave sensors between 1979 and 2020, and analytical techniques, including partial correlation, ridge regression, path analysis, and machine learning, we explored the responses of SOF to multiple climate change factors, including warming (surface and air temperature), start date of permafrost thawing (SOT), soil properties (soil temperature and volume of water), and the snow depth water equivalent (SDWE). Overall, climate warming exhibited the maximum control on SOF, but SOT in spring was also an important driver of SOF variability; among the 65.9% significant SOT and SOF correlations, 79.3% were positive, indicating an overall earlier thawing would contribute to an earlier frozen in winter. The machine learning analysis also suggested that apart from warming, SOT ranked as the second most important determinant of SOF. Therefore, we identified the mechanism responsible for the SOT-SOF relationship using the SEM analysis, which revealed that soil temperature change exhibited the maximum effect on this relationship, irrespective of the permafrost type. Finally, we analyzed the temporal changes in these responses using the moving window approach and found increased effect of soil warming on SOF. In conclusion, these results provide important insights into understanding and predicting SOF variations with future climate change.

A miRNA-205-based model for prediction of the recurrence of endometrioid endometrial cancer.

AIM: To develop a miRNA-205 based model for prediction of the recurrence of endometrial cancer. METHODS: The FIGO (International Federation of Gynecology and Obstetrics) stage, grading, myometrial infiltration, lymph node status and miRNA-205 expression levels were extracted from 90 endometrioid endometrial cancer patients, recurrence related risk factors were analyzed by Cox regression analysis. A risk model was then developed. RESULTS: A total of 90 endometrial cancer patients were retrospectively included for the analysis. The FIGO stage and expression levels of miRNA 205 were independently associated with the recurrence-free survival of the patients. The FIGO stage and expression levels of miRNA 205 were used for a prognostic model of recurrence-free survival. The c-index of the model reached 0.764, and the output of the model (risk score) could stratify the patients into different groups on the risk of recurrence. CONCLUSION: A miRNA-205 based model could predict the risk of recurrence for endometrioid endometrial cancer, and the model could provide a risk stratification of patients by recurrence risk.

Determination of polymyxin B in human plasma and epithelial lining fluid using LC-MS/MS and its clinical application in therapeutic drug monitoring.

Polymyxin B (PB) is currently one of the last resort treatment options against carbapenem-resistant gram-negative bacterial pathogens. Pharmacokinetics/pharmacodynamics (PK/PD) guided therapeutic drug monitoring (TDM) of antibiotics is critical for optimizing dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. Currently, methods for determining PB in human plasma and epithelial lining fluid (ELF) are limited. In this study, we developed and validated a simple method for PB determination in human plasma and ELF using LC-MS/MS. Protein precipitation of the sample was conducted with 0.1% formic acid-acetonitrile. Polymyxin B1 and B2 were separated on a C18 column and detected within 4 min by the mass spectrometer in the positive mode coupled with multiple reaction monitoring. The calibration curve range was 0.156-10.0 and 0.0156-1.00 µg/mL in the plasma for polymyxin B1 and B2, respectively, and was 0.0625-2.00 and 0.00625-0.200 µg/mL for polymyxin B1 and B2, respectively in bronchoalveolar lavage fluid. The accuracy of the intra- and inter-assay studies ranged from 80.6% to 114.9%, and the coefficients of variation for intra- and inter-day assays were less than 14.8%. Among a considerable number of patients, the average steady-state plasma concentration of PB was suboptimal. Moreover, the exposure to PB in patients with acute kidney injury (AKI) was considerably higher than that in patients without AKI. Meanwhile, a higher concentration of PB in ELF could be achieved than that in plasma after PB nebulization treatment. The established method was proven to be rapid, simple, and suitable for TDM of PB and PK/PD studies in human plasma and ELF.

Contrasting responses of peak vegetation growth to asymmetric warming: Evidences from FLUXNET and satellite observations.

The peak growth of plant in summer is an important indicator of the capacity of terrestrial ecosystem productivity, and ongoing studies have shown its responses to climate warming as represented in the mean temperature. However, the impacts from the asymmetrical warming, that is, different rates in the changes of daytime (Tmax ) and nighttime (Tmin ) warming were mostly ignored. Using 60 flux sites (674 site-year in total) measurements and satellite observations from two independent satellite platforms (Global Inventory Monitoring and Modeling Studies [1982-2015]; MODIS [2000-2020]) over the Northern Hemisphere (≥30°N), here we show that the peak growth, as represented by both flux-based maximum primary productivity and the maximum greenness indices (maximum normalized difference vegetation index and enhanced vegetation index), responded oppositely to daytime and nighttime warming. T max - T min + (peak growth showed negative responses to Tmax , but positive responses to Tmin ) dominated in most ecosystems and climate types, especially in water-limited ecosystems, while T max + T min - (peak growth showed positive responses to Tmax , but negative responses to Tmin ) was primarily observed in high latitude regions. These contrasting responses could be explained by the strong association between asymmetric warming and water conditions, including soil moisture, evapotranspiration/potential evapotranspiration, and the vapor pressure deficit. Our results are therefore important to the understanding of the responses of peak growth to climate change, and consequently a better representation of asymmetrical warming in future ecosystem models by differentiating the contributions between daytime and nighttime warming.

Earlier leaf senescence dates are constrained by soil moisture.

The unprecedented warming that has occurred in recent decades has led to later autumn leaf senescence dates (LSD) throughout the Northern Hemisphere. Yet, great uncertainties still exist regarding the strength of these delaying trends, especially in terms of how soil moisture affects them. Here we show that changes in soil moisture in 1982-2015 had a substantial impact on autumn LSD in one-fifth of the vegetated areas in the Northern Hemisphere (>30° N), and how it contributed more to LSD variability than either temperature, precipitation or radiation. We developed a new model based on soil-moisture-constrained cooling degree days (CDDSM ) to characterize the effects of soil moisture on LSD and compared its performance with the CDD, Delpierre and spring-influenced autumn models. We show that the CDDSM model with inputs of temperature and soil moisture outperformed the three other models for LSD modelling and had an overall higher correlation coefficient (R), a lower root mean square error and lower Akaike information criterion (AIC) between observations and model predictions. These improvements were particularly evident in arid and semi-arid regions. We studied future LSD using the CDDSM model under two scenarios (SSP126 and SSP585) and found that predicted LSD was 4.1 ± 1.4 days and 5.8 ± 2.8 days earlier under SSP126 and SSP585, respectively, than other models for the end of this century. Our study therefore reveals the importance of soil moisture in regulating autumn LSD and, in particular, highlights how coupling this effect with LSD models can improve simulations of the response of vegetation phenology to future climate change.

Mesenchymal Stem Cell Derived Exosomes as Nanodrug Carrier of Doxorubicin for Targeted Osteosarcoma Therapy via SDF1-CXCR4 Axis.

Purpose: The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and exosome (Exo-Dox) derived from mesenchymal stem cells in vitro and in vivo. Methods: The exosomes were isolated with Exosome Isolation Kit, and the Exo-Dox was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The exosome and Exo-Dox were examined by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). The antitumor activity, targeting capability, and mechanism of the developed Exo-Dox were evaluated by cell viability assay, histological and immunofluorescence analysis and in vivo imaging system. Results: NTA results showed the size of the exosomes had increased from 141.6 nm to 178.1 nm after loading with doxorubicin. Compared with free Dox, the Exo-Dox exhibited higher cytotoxicity against osteosarcoma MG63 cells, HOS cells, and 143B cells than free Dox, the half-maximal inhibitory concentrations (IC50) of Dox, Exo-Dox were calculated to be 0.178 and 0.078 µg mL-1 in MG63 cells, 0.294 and 0.109µg mL-1 in HOS cells, 0.315 and 0.123 µg mL-1 in 143B cells, respectively. The in vivo imaging showed that MSC derived Exo could serve as a highly efficient delivery vehicle for targeted drug delivery. The immunohistochemistry and histology analysis indicated that compared with the free Dox group, the Ki67-positive cells and cardiotoxicity in Exo-Dox group were significantly decreased. Conclusion: Our results suggested that MSC-derived Exo could be excellent nanocarriers used to deliver chemotherapeutic drug Dox specifically and efficiently in osteosarcoma, resulting in enhanced toxicity against osteosarcoma and less toxicity in heart tissue. We further demonstrated the targeting capability of Exo was due to the chemotaxis of MSC-derived exosomes to osteosarcoma cells via SDF1-CXCR4 axis.

Winter warming offsets one half of the spring warming effects on leaf unfolding.

Winter temperature-related chilling and spring temperature-related forcing are two major environmental cues shaping the leaf-out date of temperate species. To what degree insufficient chilling caused by winter warming would slow phenological responses to spring warming remains unclear. Using 27,071 time series of leaf-out dates for 16 tree species in Europe, we constructed a phenological model based on the linear or exponential function between the chilling accumulation (CA) and forcing requirements (FR) of leaf-out. We further used the phenological model to quantify the relative contributions of chilling and forcing on past and future spring phenological change. The results showed that the delaying effect of decreased chilling on the leaf-out date was prevalent in natural conditions, as more than 99% of time series exhibited a negative relationship between CA and FR. The reduction in chilling linked to winter warming from 1951 to 2014 could offset about one half of the spring phenological advance caused by the increase in forcing. In future warming scenarios, if the same model is used and a linear, stable correlation between CA and FR is assumed, declining chilling will continuously offset the advance of leaf-out to a similar degree. Our study stresses the importance of assessing the antagonistic effects of winter and spring warming on leaf-out phenology.