Increasing riverine export of dissolved organic carbon from China.

River transport of dissolved organic carbon (DOC) to the ocean is a crucial but poorly quantified regional carbon cycle component. Large uncertainties remaining on the riverine DOC export from China, as well as its trend and drivers of change, have challenged the reconciliation between atmosphere-based and land-based estimates of China's land carbon sink. Here, we harmonized a large database of riverine in-situ measurements and applied a random forest model, to quantify riverine DOC fluxes (FDOC ) and DOC concentrations (CDOC ) in rivers across China. This study proposes the first DOC modeling effort capable of reproducing well the magnitude of riverine CDOC and FDOC , as well as its trends, on a monthly scale and with a much wider spatial distribution over China compared to previous studies that mainly focused on annual-scale estimates and large rivers. Results show that over the period 2001-2015, the average CDOC was 2.25 ± 0.45 mg/L and average FDOC was 4.04 ± 1.02 Tg/year. Simultaneously, we found a significant increase in FDOC (+0.044 Tg/year2 , p = .01), but little change in CDOC (-0.001 mg/L/year, p > .10). Although the trend in CDOC is not significant at the country scale, it is significantly increasing in the Yangtze River Basin and Huaihe River Basin (0.005 and 0.013 mg/L/year, p < .05) while significantly decreasing in the Yellow River Basin and Southwest Rivers Basin (-0.043 and -0.014 mg/L/year, p = .01). Changes in hydrology, play a stronger role than direct impacts of anthropogenic activities in determining the spatio-temporal variability of FDOC and CDOC across China. However, and in contrast with other basins, the significant increase in CDOC in the Yangtze River Basin and Huaihe River Basin is attributable to direct anthropogenic activities. Given the dominance of hydrology in driving FDOC , the increase in FDOC is likely to continue under the projected increase in river discharge over China resulting from a future wetter climate.

Nucleic Acid-Scavenging Hydrogels Accelerate Diabetic Wound Healing.

Chronic inflammation is a typical feature and a major impediment in refractory diabetic foot ulcer (DFU). High levels of extracellular cell-free nucleic acid (cfDNA) have recently been known to play a critical role in the cause of inflammation. Herein, we fabricated polyacrylamide-based cationic hydrogels and topically applied them to the ulcer of a diabetic rat model. The cfDNA level in the wound area was significantly reduced after hydrogel adsorption, and the level of inflammation was eliminated. In turn, the wound closure was significantly promoted without introducing systemic toxicity. Cationic hydrogels represent an effective material to combat uncontrolled inflammation in DFU.

Consistent time allocation fraction to vegetation green-up versus senescence across northern ecosystems despite recent climate change.

Extended growing season lengths under climatic warming suggest increased time for plant growth. However, research has focused on climatic impacts to the timing or duration of distinct phenological events. Comparatively little is known about impacts to the relative time allocation to distinct phenological events, for example, the proportion of time dedicated to leaf growth versus senescence. We use multiple satellite and ground-based observations to show that, despite recent climate change during 2001 to 2020, the ratio of time allocated to vegetation green-up over senescence has remained stable [1.27 (± 0.92)] across more than 83% of northern ecosystems. This stability is independent of changes in growing season lengths and is caused by widespread positive relationships among vegetation phenological events; longer vegetation green-up results in longer vegetation senescence. These empirical observations were also partly reproduced by 13 dynamic global vegetation models. Our work demonstrates an intrinsic biotic control to vegetation phenology that could explain the timing of vegetation senescence under climate change.

Nanoparticulate DNA scavenger loading methotrexate targets articular inflammation to enhance rheumatoid arthritis treatment.

Abnormal high cell-free DNA (cfDNA) activates toll-like receptor 9 (TLR9) in immune cell's endosome to produce inflammatory cytokines that aggravate rheumatoid arthritis (RA). Previously, we successfully developed cationic nanoparticles (cNPs) relieving symptoms of RA rats by scavenging cfDNA, but the strong positive charges of cNPs may cause systemic toxicity during circulation via intravenous injection. Herein, we design cNP-pp-PEG to shield the nanoparticles with MMP2-sensitive peptide (pp) linked PEG, the cations are exposed only when PEG is removed by MMP2, which is enriched in the inflamed articular cavity. Taking advantage of the self-assembled cNP-pp-PEG, hydrophobic methotrexate (MTX) is loaded into its core through hydrophobicity interaction, obtaining MTX@cNP-pp-PEG. The engineered reagents exhibit lower toxicity, longer retention time and higher accumulation in inflamed joints comparing to its counterpart MTX@cNP-pp due to the hidden cationic charges. Moreover, the anti-inflamed activity of MTX strengthens the therapeutic efficiency of cNPs. The dual roles of cNPs as therapeutic agent and MTX carrier significantly enhance the therapeutic efficacy and extended administration interval to 4 days. This research addresses the issues of targeting inflamed joints, reducing the systemic toxicities of both cNPs and MTX, and extending administration interval, demonstrating an upgraded strategy for DNA scavenger application.

The protein corona modulates the inflammation inhibition by cationic nanoparticles via cell-free DNA scavenging.

A central paradigm in nanomedicine is that when synthetic nanoparticles (NPs) enter the body, they are immediately cloaked by a corona of macromolecules (mostly proteins) that mediates the role of the physico-chemical properties in the NP biological functions (the "coronation paradigm"). In this work, we focused on the assessment of the "coronation paradigm" for cationic NPs (cNPs) used as rheumatoid arthritis (RA) drugs due to their ability to scavenge cell-free DNA (cfDNA). We fabricated series of cNPs uniformly coated with single or di-hydroxyl groups and different types of amino groups and showed that hydroxylated nanoparticles displayed a prolonged retention in inflamed joints and greater anti-inflammatory effect in collagen-induced arthritis (CIA) rats than the non-hydroxylated analogues. Especially, the cNPs with secondary amines and a di-hydroxyl shell showed the best performance among the tested cNPs. Proteomic analysis showed that the cNPs with a di-hydroxyl shell adsorbed less opsonin proteins than the cNPs carrying mono hydroxyl groups and non-hydroxylated ones, which may provide a mechanistic explanation for the different biodistribution profiles of cNPs. Thus, this study suggests that the protein corona mediates the effects of the surface chemistry on the fate and functions of cNPs as anti-RA drugs.

Self-degradable poly(ß-amino ester)s promote endosomal escape of antigen and agonist.

Vaccination with subunit nanovaccines is a promising strategy to combat virus infection and tumor development. However, immunogenicity of present nanovaccines is still unsatisfied for clinical translation. Here, we developed a nanovaccine loading a STING agonist, 2'3'-cGAMP and, a model subunit antigen, OVA, by using a well-defined self-degradable poly(ß-amino ester)s to treat B16F10-OVA melanoma tumors. The polymer underwent slow hydrolysis at pH 5.5 but self-degraded induced by the amino groups along the polyester chain at pH > 6.5. It is shown that the self-degradation products facilitated the release of 2'3'-cGAMP and OVA from early endolysome to the cytosol, where the two components strongly activated CD8+ T lymphocytes (CTLs) and significantly enhanced Ifn1, TNF, Cxcl9, and Cxcl10 expression. In turn, the tumor microenvironment was remolded from cold to hot. Moreover, the nanovaccine could be quickly drained to sentinel lymph nodes after intratumoral injection. The nanovaccine with strong immunogenicity also could reduce the side effects of systemic inflammatory reaction caused by molecular 2'3'-cGAMP. The tumor progression of animals was inhibited, and their survival rates increased significantly. Thus, the multifunctional biodegradable material provided a new delivery system for a cancer vaccine to translate to clinics.

Topical cationic hairy particles targeting cell free DNA in dermis enhance treatment of psoriasis.

Abnormal high level of cell free DNA (cfDNA) triggers chronic inflammation to exacerbate psoriasis symptoms. Scavenging cfDNA by topical cationic polymeric nanoparticles has been certified as an effective therapeutic strategy for treating psoriasis. However, cationic cfDNA scavengers have a great potential risk to organs after entering systemic circulation through skin barrier. For better transformation to clinical application, herein a series of poly(2-(dimethylamino)ethyl methacrylate) (PDMA) grafted hairy silica particles (cSPs) with tunable PDMA length and particle size are applied to scavenge cfDNA in dermis. We reveal that the structure of cSPs correlates with the permeation ability across stratum corneum, retention time in dermis, binding affinity to cfDNA, and toxicity tolerance, which in turn affect the therapeutic effect. Especially, the cSPs of 700 nm show more accumulation and longer retention in psoriatic lesions, leading to excellent treatment results. They also outperform the cSPs of 200 nm at a lower administration frequency. Thus, we address the issues of size, cationic content of cSPs to open a potential new avenue to topically treatment of psoriasis by targeting cfDNA in dermis.

Topical nanoparticles interfering with the DNA-LL37 complex to alleviate psoriatic inflammation in mice and monkeys.

Cell-free DNA (cfDNA) released from damaged or dead cells combines with LL37 and is converted into an immune response activator to exacerbate psoriasis. Here, we show that cationic nanoparticles (cNPs) efficiently compete for DNA from the DNA-LL37 immunocomplex and inhibit DNA-LL37-induced cell activation. Using phenotypical images, psoriasis area and severity index scoring, histology, and immunohistochemical analysis, we demonstrate that topical application of cNPs on psoriasiform skin of a mouse model relieves psoriatic symptoms. It is noteworthy that the results were confirmed in a cynomolgus monkey model. Moreover, topically administrated cNPs showed low in vivo toxicity because of their retention in skin. Mechanistic analyses of cytokine expression in the psoriatic site, cfDNA levels in circulation and inflamed skin, skin permeation, and biodistribution of cNPs also matched the therapeutic outcomes. Therefore, we present a previously unidentified strategy of nanomedicine to treat skin inflammatory diseases, which demonstrates great potential for clinical application.