River-lake systems, crucial to both the ecological environment and societal development, have been affected by increasing anthropogenic activities in addition to climate and environmental changes. ...Here, annual water discharge and sediment load data (1956–2017) and rainfall data (1960–2016) from Dongting Lake in the middle catchment of the Yangtze River were analysed at four major inlets and one outlet, and their connections with lake level variations were evaluated using multiple analytical methods. The results show that minor fluctuations were found in rainfall and discharge during the study period, but the sediment load entering Dongting Lake decreased significantly from 231 mt/year (before 1969) to 123 mt/year (1970–2002) and then 17 mt/year (after 2003, post TGD). The variation in the sediment was mainly induced by increasing anthropogenic activities in the lake system. During period 1 (before 1969), human impact was weak compared to the dominant natural forces. However, anthropogenic force showed an increasing contribution to the loss of sediment load since then, as it increased from 43.0% (1970–1987, post cut-off engineering) to 64.8% (1988–2002, post Gezhou Dam) and extended to 90.2% during 2003–2017 (post TGD). Nevertheless, continuous sediment accumulation over the past decades in the lake has caused a rising water level. During period 1, high sediment input contributed to an average annual increase of 13.96 cm in the lake level, but it decreased significantly to 1.94 cm year−1 during 1970–2002 due to intensive anthropogenic regulations. Since 2003, the completion of the TGD intercepted abundant sediment, eventually leading to a shift from net deposition to net loss of the sediment budget in Dongting Lake, and consequently, the lake level fell. In the future, if the net sediment supply was kept below ~18 mt/year, the lake level would continue to fall, causing severe problems to the lake ecosystem, especially during drought years.
•We observed significant lowering trend of water level in Dongting Lake in the past decade.•Fluctuation of sediment budget into the Dongting lake is critical for water level variation.•Anthropogenic activities contribute 90.6% of reduction of sediment load in the Dongting Lake.•Lake bed incision due to construction of TGD is the main cause for the lowering lake level.
Understanding the evolution and driving factors of sedimentation and erosion at the mouths of small and medium-sized mountain streams during various periods is essential for regional spatial ...utilization, development, and sustainable economic growth. This is particularly important when considering the combined impact of climate change and human activities. This paper presents an analysis of the changes in sedimentation and erosion of mouth isobaths and underwater deltas over different periods using nautical chart data (1950-2019) and analyzes the factors driving changes in sedimentation and erosion during different periods from 1950 to 2020 based on the runoff-sediment discharge of the Minjiang River (MR) and extreme climate factors such as typhoons, especially the driving factors that caused a sudden change in the sedimentation and erosion process between 1998 and 2005. The results indicate that runoff-sediment characteristics are crucial in driving sedimentation and erosion changes. In the past 70 years, the underwater delta of the MRE has mainly experienced four stages: deposition (1950-1992) -erosion (1993-1998) -deposition (1998-2011) -erosion (2011-2019). Taking the impoundment operation of the Shuikou Reservoir in 1993 as the node, the sediment load of the Minjiang River into the sea began to decrease sharply, and then the estuary quickly showed a state of erosion. The change of sediment flux into the sea is the main driving factor for the evolution of erosion and deposition in the Minjiang River Estuary (MRE). The critical value of the erosion-deposition transition is about 570.3 × 10
4
t/yr. After the estuary entered a state of erosion in 1993-1998, significant siltation suddenly occurred in 1998-2005. The reason for the siltation in this period may be related to the frequent transit typhoons and flood events in 1998-2005. Therefore, the change of river sediment supply into the sea is the main driving factor controlling the erosion and deposition evolution of the Minjiang River estuary on a long time scale of more than 10 years, which reflects the influence of large-scale human activities on the river and estuary area in the past half century. Extreme climate events are the incentive to adjust the estuary landform in the short term. Extreme climate events will not fundamentally change the process of estuarine geomorphological evolution under the background of sediment supply reduction.
The present study investigates the impact of the Three Gorges Dam (TGD) construction on riverbed morphology in the middle Yangtze River (YR). We analyse data collected on sand wave morphology, ...shallow surface topography, and section morphology after the completion of the dam. Specifically, we examine the spatial distribution characteristics of sand wave morphology and the riverbed evolution process in the Yicheng reach. Results reveal significant changes in the morphology of sand waves in the middle reach of the YR, with wavelengths ranging from 5.2124.15 to 5.0915.33 m in the upper and lower Jingjiang River, respectively. Additionally, sediment incipient velocity was found to be smaller than that of the sand wave, making it difficult for the sand wave to start as the bedload continued to coarsen. After impoundment, the riverbed is strongly scoured, the undercutting is serious, and the bed morphology changes dramatically.
Extreme weather events and anthropogenic activity have severely impacted the Minjiang estuary (MJE) with evolution patterns in recent decades. Determining the estuarine alluvial evolution pattern is ...crucial for the sustainable development of densely populated coastal areas. Using chart data, this paper analyzed how the MJE's flushing and siltation changed over time (1950–2019). The findings indicate that, in the past 70 years, the MJE has evolved through seven stages of flushing and siltation under the condition of decreasing incoming sediment: “significant siltation - siltation - minor siltation - significant erosion - significant siltation - minor siltation - significant erosion”. Despite decreased incoming material, the estuary underwent substantial siltation from 1998 to 2005. Extreme meteorological conditions were the cause of this anomaly. The “severe flushing” phenomenon occurred in the study area from 2011 to 2019, and the comparison of pre-dam and post-dam at the estuary revealed that extreme weather can only adjust in stages and cannot change the overall state of the estuary flushing due to the reduction of incoming sediment in the basin. According to the EOF (Empirical Orthogonal/Eigen Function) study of four sections of the estuary, it is most impacted by incoming sediment from the watershed, followed by severe weather conditions. Our research is crucial for comprehending how human behavior and harsh weather might affect the development of MJE, and it offers sound advice for the long-term management of MJE.
Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking ...in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance cancer immunotherapy.
Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability ...has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration. In vitro studies identify that the isomannide-derived lipid nanoparticles (DIM1T LNP) efficiently deliver RNAs to ASCs. Co-delivery of self-amplifying RNA (saRNA) and E3 mRNA complex (the combination of saRNA and E3 mRNA is named SEC) using DIM1T LNP modulates host immune responses against saRNAs and facilitates the durable production of proteins of interest in ASCs. The DIM1T LNP-SEC engineered ASCs (DS-ASCs) prolong expression of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 12 (CXCL12), which show superior wound healing efficacy over their wild-type and DIM1T LNP-mRNA counterparts in the diabetic cutaneous wound model. Overall, this work suggests LNPs as an effective platform to engineer ASCs with enhanced protein generation ability, expediting the development of ASCs-based cell therapies.
Lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) COVID-19 vaccines has provided large-scale immune protection to the public. To elicit a robust immune response against SARS-CoV-2 ...infections, antigens produced by mRNAs encoding SARS-CoV-2 Spike glycoprotein need to be efficiently delivered and presented to antigen-presenting cells such as dendritic cells (DCs). As concurrent innate immune stimulation can facilitate the antigen presentation process, a library of non-nucleotide STING agonist-derived amino lipids (SALs) was synthesized and formulated into LNPs for mRNA delivery. SAL12 lipid nanoparticles (SAL12-LNPs) were identified as most potent in delivering mRNAs encoding the Spike glycoprotein (S) of SARS-CoV-2 while activating the STING pathway in DCs. Two doses of SAL12 S-LNPs by intramuscular immunization elicited potent neutralizing antibodies against SARS-CoV-2 in mice.
Toll‐like receptors (TLRs) and CD40‐related signaling pathways represent critical bridges between innate and adaptive immune responses. Here, an immunotherapy regimen that enables co‐stimulation of ...TLR7/8‐ and CD40‐mediated pathways is developed. TLR7/8 agonist resiquimod (R848) derived amino lipids, RAL1 and RAL2, are synthesized and formulated into RAL‐derived lipid nanoparticles (RAL‐LNPs). The RAL2‐LNPs show efficient CD40 mRNA delivery to DCs both in vitro (90.8 ± 2.7%) and in vivo (61.3 ± 16.4%). When combined with agonistic anti‐CD40 antibody, this approach can produce effective antitumor activities in mouse melanoma tumor models, thereby suppressing tumor growth, prolonging mouse survival, and establishing antitumor memory immunity. Overall, RAL2‐LNPs provide a novel platform toward cancer immunotherapy by integrating innate and adaptive immunity.
TLR7/8 agonist R848‐derived amino lipid nanoparticle (RAL‐LNP) is conceived to deliver CD40 mRNA to dendritic cells (DCs) in the tumor microenvironment to increase CD40 expression on DCs. Further combination with agonistic CD40 antibodies enables the synergistic effects of TLR7/8 and CD40 signaling pathways for DC maturation and activation, thereby promoting antitumor immunity.
Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a ...formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.
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