Procedurally Targeted Delivery of Antitumor Drugs Using FAPα-Responsive TPGS Dimer-Based Flower-like Polymeric Micelles.

To overcome the intestinal epithelium barrier and achieve a better antitumor effect, the procedurally targeting flower-like nanomicelles for oral delivery of antitumor drugs were designed based on FAPα-responsive TPGS1000 dimer (TPGS-Gly-Pro-TPGS) and L-carnitine linked poly(2-ethyl-2-oxazoline)-b-poly(D, l-lactide) (Car-PEOz-b-PLA). As expected, compared with unmodified polymeric micelles (TT-PMs) composed of TPGS-Gly-Pro-TPGS, L-carnitine conjugated polymeric micelles (CTT-PMs) formed from both TPGS-Gly-Pro-TPGS and Car-PEOz-b-PLA with favorable stability in simulated gastrointestinal fluid and FAPα-dependent release capability exhibited remarkably enhanced cellular uptake and transmembrane transport through OCTN2 mediation confirmed by fluorescence immunoassay, which was intuitively evidenced by stronger fluorescence within epithelial cells, and the basal side of small intestinal epithelium of mice being given intragastric administration of DiI-labeled micelles. The transport of CTT-PMs across the intestinal epithelium in an intact form was mediated by clathrin along the intracellular transport pathway of endosome-lysosome-ER-Golgi apparatus. Furthermore, both the increased uptake by FAPα-positive U87MG cells and unchangeable uptake by FAPα-negative C6 cells for coumarin-6 (C-6)/CTT-PMs compared with C-6/TT-PMs evidenced the targeting ability of CTT-PMs to FAPα-positive tumor cells. Both OCTN2-mediation and FAPα-responsiveness were beneficial for polymeric micelles to improve the delivery and therapeutic efficiency of antitumor agents, which was further supported by the remarkable enhancement in in vivo antitumor efficacy via promoting apoptosis of tumor cells for paclitaxel (PTX)-loaded CTT-PMs (PTX/CTT-PMs) with low toxicity compared with PTX/TT-PMs. Our findings offered an alternative design strategy for procedurally targeted delivery of chemotherapeutics by an oral route.

Spatial variation of soil phosphorus in the water level fluctuation zone of the Three Gorges Reservoir: Coupling effects of elevation and artificial restoration.

The water level fluctuation zone (WLFZ) is a distinctive and important component of the reservoir ecosystem. Due to periodic inundation, the fraction, spatial distribution, and chemical reactivity of soil phosphorus (P) within the WLFZ can potentially impact the loading of P into reservoir waters. However, a detailed study of this subject is lacking. In this study, the soil P in the WLFZ of the Three Gorges Reservoir, China, was examined using a combination of chemical sequential extraction, 31P NMR, and adsorption experiments. The results of chemical sequential extraction showed that HCl-Pi constituted the largest P pool among all P forms, with a mean concentration of 338 mg/kg. The content of HCl-Pi decreased significantly toward the dam, while the content of Res-P decreased in the opposite direction. The highest contents of most P forms and total P were observed at an elevation of 160 m. 31P NMR measurements showed that NaOH-EDTA Pi detectable in WLFZ soils at 145 m, 160 m, and 175 m elevation consisted mainly of orthophosphate and pyrophosphate, while NaOH-EDTA Po contained phosphate monoesters and phosphate diesters, accounting for 1.4 % to 46.2 % of NaOH-EDTA TP. Adsorption experiments showed that soil P in the WLFZ was a potential P source for reservoir waters, with chemisorption being the dominant mechanism of P sequestration. The adsorption equilibrium concentration of WLFZ soil was lower at higher elevations (>170 m) compared to lower elevations (<150 m), exhibiting a decrease in the average maximum adsorption from 271 mg/kg to 192 mg/kg. Statistical analysis suggested that Ca and Fe content, particle size, elevation, and artificial restoration were key factors affecting the fraction and content of soil P in the WLFZ. Our findings contribute to an improved understanding of the behavior of soil P in the WLFZ of large reservoirs and its potential contribution to the reservoir waters.

Sedimentary records of polycyclic aromatic hydrocarbons from three enclosed lakes in China: Response to energy structure and economic development.

Historical polycyclic aromatic hydrocarbon (PAH) pollution was explored through the sedimentary records of three lakes: Huguangyan Maar Lake (HGY) in South China, Mayinghai Lake (MYH) in North China, and Sihailongwan Lake (SHLW) in Northeast China. In these three lakes, the PAH concentrations in sediments are still rising, showing the different trend to lakes in developed countries. PAH pollution in South China occurred from 1850, much earlier than the increases since 1980 observed in North and Northeast China. The temporal trends of PAH concentrations in lake sediments are highly correlated with local economic development. Spatially, although the region where HGY is located has the highest gross domestic product, higher fluxes of PAHs were found in MYH sediments, indicating that atmospheric PAH pollution in North China might be more serious, and that PAH pollution is not fully correlated with economic development. Source analysis suggested that the PAHs in lake sediments are mainly derived from oil leaks, coal and biomass combustion, vehicle emissions, and diagenesis. Positive matrix factorization (PMF) model revealed that the contribution of vehicle emissions and coal combustion to PAHs has increased significantly in the past 40 years. Benzo(a)pyrene equivalent (BaPE) in the surface sediments of MYH and SHLW were similar and higher than in HGY. In HGY, vehicle emissions posed the highest toxic risk, followed by coal combustion. However, in MYH, the toxicity risk of vehicle emissions was close to that of coal and biomass combustion due to the highly developed coal industry in Shanxi Province. In SHLW, the contribution of fossil fuel combustion to BaPE was significantly higher than that of biomass combustion. This study provides important information for understanding PAH pollution affected by anthropogenic activities in the Anthropocene and provides a scientific basis for formulating PAH pollution control strategies.

Insecticidal activities of the essential oil of Rhynchanthus beesianus rhizomes and its constituents against two species of grain storage insects.

The aim of this research was to evaluate insecticidal activities of the essential oil of Rhynchanthus beesianus rhizomes against adults of Liposcelis entomophila and Tribolium castaneum. Gas chromatography-mass spectrometry analyses revealed the presence of 44 compounds with ß-eudesmol (19.1%), elemol (8.1%), α-terpineol (8.0%), methyl eugenol (6.5%), and caryophyllene (4.8%) being the major constituents. Bioactivity-directed chromatographic separation of the oil led to the isolation of four constituents, elemol, ß-eudesmol, methyl eugenol, and α-terpineol. The essential oil exhibited fumigant toxicity against the adults of L. entomophila and T. castaneum with LC50 values of 0.57 and 4.96 mg/L air while the two isolates, methyl eugenol and α-terpineol possessed fumigant toxicity against the booklice (LC50 = 0.15 and 0.48 mg/L air, respectively) and the beetles (LC50 = 1.81 and 4.96 mg/L air, respectively). The oil also possessed contact toxicity against the booklice and the beetles with LD50 values of 121.56 µg/cm2 and 54.93 µg/adult, respectively, while the two isolates ß-eudesmol and elemol showed contact toxicity against L. entomophila (LD50 = 99.21 and 35.19 µg/cm2, respectively) and T. castaneum (LD50 = 35.26 and 8.89 µg/adult, respectively). The results indicate that the oil of R. beesianus rhizomes and its isolates have potential as a source for natural insecticides.

Seasonal changes of trace elements, nutrients, dissolved organic matter, and coastal acidification over the largest oyster reef in the Western Mississippi Sound, USA.

Seasonal changes of trace elements, nutrients, dissolved organic matter (DOM), and carbonate system parameters were evaluated over the largest deteriorating oyster reef in the Western Mississippi Sound using data collected during spring, summer, and winter of 2018, and summer of 2019. Higher concentrations of Pb (224%), Cu (211%), Zn (2400%), and Ca (240%) were observed during winter of 2018 compared to summer 2019. Phosphate and ammonia concentrations were higher (> 800%) during both summers of 2018 and 2019 than winter of 2018. Among the three distinct DOM components identified, two terrestrial humic-like components were more abundant during both spring (12% and 36%) and summer (11% and 33%) of 2018 than winter of 2018, implying a relatively lesser supply of humic-like components from terrestrial sources during winter. On the other hand, the protein-like component was more abundant during summer of 2019 compared to rest of the study period, suggesting a higher rate of autochthonous production during summer 2019. In addition, to their significant depth-wise variation, ocean acidification parameters including pH, pCO2, CO32-, and carbonate saturation states were all higher during both summers of 2018 and 2019. The measured variables such as trace elements, organic carbon, suspended particulates, and acidification parameters exhibited conservative mixing behavior against salinity. These observations have strong implications for the health of the oyster reefs, which provides ecologically important habitats and supports the economy of the Gulf Coast.

Enhanced Oral Absorption and Liver Distribution of Polymeric Nanoparticles through Traveling the Enterohepatic Circulation Pathways of Bile Acid.

The intestinal epithelium is known to be a main hindrance to oral delivery of nanoparticles. Even though surface ligand modification can enhance cellular uptake of nanoparticles, the "easy entry and hard across" was frequently observed for many active targeting nanoparticles. Here, we fabricated polymeric nanoparticles relayed by bile acid transporters with monomethoxy poly(ethylene glycol)-poly(D,l-lactide) and deoxycholic acid-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) based on structural characteristics of intestine epithelium and the absorption characteristics of endogenous substances. As anticipated, deoxycholic acid-modified polymeric nanoparticles featuring good stability in simulated gastrointestinal fluid could notably promote the internalization of their payload by Caco-2 cells through mediation of apical sodium-dependent bile acid transporter (ASBT) and transmembrane transport of the nanoparticles across Caco-2 cell monolayers via relay-guide of ASBT, ileal bile acid-binding protein, and the heteromeric organic solute transporter (OSTα-OSTß) along with multidrug resistance-associated protein 3 (MRP3) evidenced by competitive inhibition and fluorescence immunoassay, which was further visually confirmed by the stronger fluorescence from C6-labeled nanoparticles inside enterocytes and the basal side of the intestinal epithelium of mice. The transcellular transport of deoxycholic acid-modified nanoparticles in an intact form was mediated by caveolin/lipid rafts and clathrin with intracellular trafficking trace of endosome-lysosome-ER-Golgi apparatus and bile acid transport route. Furthermore, the increased uptake by HepG2 cells compared with unmodified nanoparticles evidenced the target ability of deoxycholic acid-modified nanoparticles to the liver, which was further supported by ex vivo imaging of excised major organs of mice. Thus, this study provided a feasible and potential strategy to further enhance transepithelial transport efficiency and liver-targeted ability of nanoparticles by means of the specific enterohepatic circulation pathways of bile acid.

Subtropical estuarine carbon budget under various hydrologic extremes and implications on the lateral carbon exchange from tidal wetlands.

As coastal areas become more vulnerable to climatic impacts, the need for understanding estuarine carbon budgets with sufficient spatiotemporal resolution arises. Under various hydrologic extremes ranging from drought to hurricane-induced flooding, a mass balance model was constructed for carbon fluxes and their variabilities in four estuaries along the northwestern Gulf of Mexico (nwGOM) coast over a four-year period (2014-2018). Loading of total organic carbon (TOC) and dissolved inorganic carbon (DIC) to estuaries included riverine discharge and lateral exchange from tidal wetlands. The lateral exchanges of TOC and DIC reached 4.5 ± 5.7 and 8.9 ± 1.4 mol·C·m-2·yr-1, accounting for 86.5% and 62.7% of total TOC and DIC inputs into these estuaries, respectively. A relatively high regional CO2 efflux (4.0 ± 0.7 mol·C·m-2·yr-1) was found, which was two times the average value in North American coastal estuaries reported in the literature. Oceanic export was the major pathway for losses of TOC (5.6 ± 1.7 mol·C·m-2·yr-1, 81.2% of total) and DIC (9.9 ± 2.9 mol·C·m-2·yr-1, 69.7% of total). The carbon budget exhibited high variability in response to hydrologic changes. For example, storm or hurricane induced flooding elevated CO2 efflux by 2-10 times in short periods of time. Flood following a drought also increased lateral TOC exchange (from -3.5 ± 4.7 to 67.8 ± 17.6 mmol·C·m-2·d-1) but decreased lateral DIC exchange (from 28.9 ± 3.5 to -7.1 ± 7.6 mmol·C·m-2·d-1). The large variability of carbon budgets highlights the importance of high-resolution spatiotemporal coverage under different hydrologic conditions, and the importance of carbon contribution from tidal wetlands to coastal carbon cycling.

Record of heavy metals in Huguangyan Maar Lake sediments: Response to anthropogenic atmospheric pollution in Southern China.

The historical atmospheric heavy metal pollution of southern China over the past 200 years was explored by analyzing radiometric dating, heavy metals, and Pb isotopes from a sediment core in Huguangyan Maar Lake. Zn, Cd, Sb, Tl, and Pb in the lake are closely related to anthropogenic activities, while Cr and Ni are mainly derived from the weathering of basalt surrounding the lake. Atmospheric Zn, Cd, Sb, and Tl increased rapidly after 1980, consistent with the local industrial development. The increase of atmospheric Pb in southern China occurred earlier than in other regions of China, with the increase after 1850. War and the use of leaded gasoline were the main causes for the rapid increase in atmospheric Pb during 1910-1950. From 1950 to 2000, the input of Pb from anthropogenic activities decreased gradually due to the stable social environment. After 2000, atmospheric Pb continued to rise due to continued industrial development. The three-end-member model of Pb isotopes indicates that coal combustion is the main source of current atmospheric Pb. The proportion of Pb derived from vehicle exhaust emissions reached a peak in the 1960s, then gradually decreased and further reduced with the ban on leaded gasoline after 2000. These results are important in identifying the sources of atmospheric heavy metal pollution and in formulating pollution control strategies.

8-(Methyltosylaminoethynyl)-1-naphthyl (MTAEN) Glycosides: Potent Donors in Glycosides Synthesis.

With 8-(methyltosylaminoethynyl)-1-naphthyl (MTAEN) glycoside as donors, a novel and efficient glycosylation protocol has been established. The MTAEN glycosylation protocol exhibits the merits of shelf-stable donors, mild catalytic promotion conditions, considerably extended substrate scope encompassing both free alcohols, silylated alcohols, nucleobases, primary amides, and C-type nucleophile acceptors, and applicability to various one-pot strategies for highly efficient synthesis of oligosaccharides, such as orthogonal one-pot, single-catalyst one-pot, and acceptor reactivity-controlled one-pot strategies.

Experimental validation of an energy balance approach for design of horizontal lifeline systems.

The energy balance approach is one of the design approaches approved in fall protection standards Z359.6, Z259.16 and SS 607 to ensure that horizontal lifeline systems (HLLSs) are adequately designed. However, this study found that theoretical calculations predicting the total fall distance (hTFD) and maximum arrest load (MAL) using an energy balance approach need to be corrected before they can be used safely. Based on the data from 48 drop tests, the authors determined that energy balance calculations differ significantly from the empirical hTFD and MAL values of HLLSs. As a result, further correction factors are introduced into the theoretical calculations to estimate hTFD and MAL conservatively. These correction factors are estimated from a regression equation derived based on experimental results and theoretical calculations.

Stromal Barrier-Dismantled Nanodrill-Like and Cancer Cell-Targeted pH-Responsive Polymeric Micelles for Further Enhancing the Anticancer Efficacy of Doxorubicin.

Cancer-associated fibroblasts (CAFs) were believed to establish a tight physical barrier and a dense scaffold for tumor cells to make them maintain immunosuppression and drug resistance, strongly hindering nanoparticles to penetrate into the core of tumor tissues and limiting the performance of tumor cell-targeted nanoparticles. Here, we fabricated the substrate Z-Gly-Pro of fibroblast activation protein α (FAPα) and folic acid-codecorated pH-responsive polymeric micelles (dual ligand-modified PEOz-PLA polymeric micelles, DL-PP-PMs) that possessed nanodrill and tumor cell-targeted functions based on Z-Gly-pro-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) (ZGP-PEOz-PLA), folic acid (FA)-conjugated PEOz-PLA (FA-PEOz-PLA), and PEOz-PLA for cancer therapy. The micelles with about 40 nm particle size and a narrow distribution exhibited favorable pH-activated endo/lysosome escape induced by their pH responsibility. In addition, the enhancement of in vitro cellular uptake and cytotoxicity to folate receptors or FAPα-positive cells for doxorubicin (DOX)/DL-PP-PMs compared with DOX/PP-PMs evidenced the dual target ability of DOX/DL-PP-PMs, which was further supported by in vivo biodistribution results. As expected, in the human oral epidermal carcinoma (KB) cells xenograft nude mice model, the remarkable enhancement of antitumor efficacy for DOX/DL-PP-PMs with low toxicity was observed compared with DOX/FA-PP-PMs and DOX/ZGP-PP-PMs. The possible mechanism was elucidated to be the dismantling of the stromal barrier by nanodrill-like DOX/DL-PP-PMs via the deletion of CAFs evidenced by the downregulation of α-SMA and inhibition of their functions proved by the decrease in the microvascular density labeled with CD31 and the reduction in the extracellular matrix detected by the collagen content, thereby promoting tumor penetration and enhancing their uptake by tumor cells. The present research offered an alternative approach integrating anticancer and antifibrosis effects in one delivery system to enhance the delivery efficiency and therapeutic efficacy of anticancer drugs.

Protective effect of Achyranthes bidentata polypeptides on NMDA-mediated injury is developmentally regulated via modulating NR2A and NR2B differentially.

BACKGROUND: Achyranthes bidentata polypeptides (ABPPs) are a potent intervention for excitotoxicity-related disorders such as Parkinson's disease and ischemic stroke. Previous work suggests that overstimulation of N-methyl-D-aspartate (NMDA) receptors plays a critical role in excitotoxicity, and expression of NR2 subunit variations is developmentally regulated. Our current study focused on neuroprotection of ABPPs on cultured neurons by modulation of NR2A and NR2B differentially. METHODS: Primary cultured neurons were treated with NVP-AAM077, Ro-256981, ABPPs, and then the neurons were exposed to NMDA to induce excitotoxicity. Cellular viability was detected promptly and 24-hour after exposure to NMDA by MTT assay. Patch-clamp recording was applied to evaluate the effect of ABPPs on NMDA-evoked current and the differential modulation of ABPPs on NR2A and NR2B subunits in conjunction with NVP-AAM077 and Ro-256981. RESULTS: ABPPs (10 µg/mL) blocked neuronal injury by NMDA in mature cultures, and the peptides conferred neuroprotection in immature cultures unless co-applied with NVP-AAM077. Furthermore, ABPPs enhanced NMDA current in mature cultures, while decreasing NMDA current in immature cultures. On the other hand, we showed that ABPPs increased NMDA current when Ro-256981 was present and decreased NMDA current when NVP-AAM007 was present. CONCLUSIONS: Neuroprotection of ABPPs on NMDA-mediated injury differentially in immature and mature cultures involves enhancement of NR2A subunits and prevention of NR2B subunits, indicating that dosage of ABPP should be considered in treatment with patients at different developmental stages.

Integrating High-Resolution Coastal Acidification Monitoring Data Across Seven United States Estuaries.

Beginning in 2015, the United States Environmental Protection Agency's (EPA's) National Estuary Program (NEP) started a collaboration with partners in seven estuaries along the East Coast (Barnegat Bay; Casco Bay), West Coast (Santa Monica Bay; San Francisco Bay; Tillamook Bay), and the Gulf of Mexico (GOM) Coast (Tampa Bay; Mission-Aransas Estuary) of the United States to expand the use of autonomous monitoring of partial pressure of carbon dioxide (pCO2) and pH. Analysis of high-frequency (hourly to sub-hourly) coastal acidification data including pCO2, pH, temperature, salinity, and dissolved oxygen (DO) indicate that the sensors effectively captured key parameter measurements under challenging environmental conditions, allowing for an initial characterization of daily to seasonal trends in carbonate chemistry across a range of estuarine settings. Multi-year monitoring showed that across all water bodies temperature and pCO2 covaried, suggesting that pCO2 variability was governed, in part, by seasonal temperature changes with average pCO2 being lower in cooler, winter months and higher in warmer, summer months. Furthermore, the timing of seasonal shifts towards increasing (or decreasing) pCO2 varied by location and appears to be related to regional climate conditions. Specifically, pCO2 increases began earlier in the year in warmer water, lower latitude water bodies in the GOM (Tampa Bay; Mission-Aransas Estuary) as compared with cooler water, higher latitude water bodies in the northeast (Barnegat Bay; Casco Bay), and upwelling-influenced West Coast water bodies (Tillamook Bay; Santa Monica Bay; San Francisco Bay). Results suggest that both thermal and non-thermal influences are important drivers of pCO2 in Tampa Bay oxygen, National Estuary Program and Mission-Aransas Estuary. Conversely, non-thermal processes, most notably the biogeochemical structure of coastal upwelling, appear to be largely responsible for the observed pCO2 values in West Coast water bodies. The co-occurrence of high salinity, high pCO2, low DO, and low temperature water in Santa Monica Bay and San Francisco Bay characterize the coastal upwelling paradigm that is also evident in Tillamook Bay when upwelling dominates freshwater runoff and local processes. These data demonstrate that high-quality carbonate chemistry observations can be recorded from estuarine environments using autonomous sensors originally designed for open-ocean settings.

Multi pH-sensitive polymer-drug conjugate mixed micelles for efficient co-delivery of doxorubicin and curcumin to synergistically suppress tumor metastasis.

Combination therapy has been proved to be an effective strategy to inhibit metastasis, however, its efficacy is always compromised by the poor delivery efficiency of drugs. In this study, multi pH-sensitive polymer-drug conjugate mixed micelles were fabricated by the self-assembly of PEOz-PLA-ace-Cur, a conjugate of curcumin (Cur) with poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) through the linkage of the pH-cleavable acetal bond, and PEOz-PLA-imi-DOX, a conjugate of doxorubicin (DOX) with PEOz-PLA through the linkage of the pH-cleavable benzoic imine bond. The mixed conjugate micelles (PP-Cur/PP-DOX-Mix-PMs) with accurately and conveniently controlled mass ratio of the two drugs were demonstrated to have a small particle size (40-128 nm), high drug loading capacity and pH-dependent drug release behavior. Notably, PP-Cur5/PP-DOX1-Mix-PMs exhibited slower DOX release under physiological conditions compared with PEOz-PLA-imi-DOX micelles, resulting in deeply reduced side effects in vivo. Furthermore, the mixed conjugate micelles showed synergistically enhanced inhibition of MDA-MB-231 cell growth and metastasis evidenced by the results of in vitro anti-invasion, wound healing and anti-migration assessment, and in vivo bioluminescence imaging in nude mice, and significant reduction of the side effects of DOX compared with dual drug physically loaded polymeric micelles. Mechanistic studies demonstrated that the possible inhibitory mechanism of PP-Cur5/PP-DOX1-Mix-PMs on tumor metastasis could be assigned to their inhibition of the invasion, migration, intravasation and extravasation of tumor cells. In conclusion, the multi pH-sensitive polymer-drug conjugate mixed micelles with synergistically enhanced anti-tumor and anti-metastasis activity are potential candidates for safe and effective cancer combination therapy.

Assessment of Endovascular Treatment for Acute Basilar Artery Occlusion via a Nationwide Prospective Registry.

Importance: Several randomized clinical trials have recently established the safety and efficacy of endovascular treatment (EVT) of acute ischemic stroke in the anterior circulation. However, it remains uncertain whether patients with acute basilar artery occlusion (BAO) benefit from EVT. Objective: To evaluate the association between EVT and clinical outcomes of patients with acute BAO. Design, Setting, and Participants: This nonrandomized cohort study, the EVT for Acute Basilar Artery Occlusion Study (BASILAR) study, was a nationwide prospective registry of consecutive patients presenting with an acute, symptomatic, radiologically confirmed BAO to 47 comprehensive stroke centers across 15 provinces in China between January 2014 and May 2019. Patients with acute BAO within 24 hours of estimated occlusion time were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. Main Outcomes and Measures: The primary outcome was the improvement in modified Rankin Scale scores (range, 0 to 6 points, with higher scores indicating greater disability) at 90 days across the 2 groups assessed as a common odds ratio using ordinal logistic regression shift analysis, adjusted for prespecified prognostic factors. The secondary efficacy outcome was the rate of favorable functional outcomes defined as modified Rankin Scale scores of 3 or less (indicating an ability to walk unassisted) at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage and 90-day mortality. Results: A total of 1254 patients were assessed, and 829 patients (of whom 612 were men [73.8%]; median [interquartile] age, 65 [57-74] years) were recruited into the study. Of these, 647 were treated with standard medical treatment plus EVT and 182 with standard medical treatment alone. Ninety-day functional outcomes were substantially improved by EVT (adjusted common odds ratio, 3.08 [95% CI, 2.09-4.55]; P < .001). Moreover, EVT was associated with a significantly higher rate of 90-day modified Rankin Scale scores of 3 or less (adjusted odds ratio, 4.70 [95% CI, 2.53-8.75]; P < .001) and a lower rate of 90-day mortality (adjusted odds ratio, 2.93 [95% CI, 1.95-4.40]; P < .001) despite an increase in symptomatic intracerebral hemorrhage (45 of 636 patients [7.1%] vs 1 of 182 patients [0.5%]; P < .001). Conclusions and Relevance: Among patients with acute BAO, EVT administered within 24 hours of estimated occlusion time is associated with better functional outcomes and reduced mortality.

Further Enhancement in Intestinal Absorption of Paclitaxel by Using Transferrin-Modified Paclitaxel Nanocrystals.

The intestinal epithelium is considered to be a major obstacle to the gastrointestinal administration for water-insoluble drugs. To enhance the intestinal absorption of paclitaxel by improving its solubility and overcoming the intestinal epithelium barrier, transferrin-modified paclitaxel nanocrystals were prepared based on the specific transferrin receptor expressed on the apical membrane of the intestinal epithelium and examined to exhibit a mean size of around 178 nm, a rod-like morphology, a sustained release property, and an enhanced in vitro antitumor effect. The in situ intestinal perfusion study proved that the intestinal absorption of transferrin-modified paclitaxel nanocrystals was remarkably enhanced compared with that of Taxol and unmodified paclitaxel nanocrystals, which was further evidenced by the result of pharmacokinetic study. Their transcytosis pathway and intracellular trafficking track were disclosed using Caco-2 cell monolayers. The transcytosis of transferrin-modified paclitaxel nanocrystals and unmodified paclitaxel nanocrystals was principally mediated by clathrin and lipid rafts. The colocalization of both paclitaxel nanocrystals with the organelles observed under confocal microscopy suggested that the late endosomes, lysosomes, ER, and Golgi apparatus played a part in the transcellular transport of both paclitaxel nanocrystals during their transcytosis. Therefore, the designed transferrin-modified drug nanocrystals might have a great potential in the enhancement of intestinal absorption of water-insoluble drugs.

Intestinal oligopeptide transporter PepT1-targeted polymeric micelles for further enhancing the oral absorption of water-insoluble agents.

The intestinal epithelium is the main barrier for nanocarriers to orally deliver poorly water-soluble and absorbed agents. To further improve the transmembrane transport efficiency of polymeric micelles, intestinal oligopeptide transporter PepT1-targeted polymeric micelles were fabricated by Gly-Sar-conjugated poly(ethylene glycol)-poly(d,l-lactic acid). The functionalized polymeric micelles with about 40 nm diameter, uniform spherical morphology and favorable cytocompatibility with Caco-2 cells were demonstrated to distinctly enhance the cellular uptake and transmembrane transport of the loaded agents. The results of intestinal absorption strongly evidenced the higher accumulation of the micelles inside the epithelial cells, at the apical and basolateral sides of the epithelium within the villi in mice. Furthermore, the interaction of Gly-Sar decorated polymeric micelles with PepT1 was explored to promote the internalization of the micelles through fluorescence immunoassay, and the PepT1 level on the membrane of Caco-2 cells treated with the micelles appeared to change in a distinctly time-dependent manner. Both clathrin- and caveolae-mediated pathways were involved in the transcellular transport for undecorated polymeric micelles, while the transcellular transport pathway for Gly-Sar decorated ones was changed to be mainly mediated by clathrin and lipid rafts. The colocalization of Gly-Sar decorated micelles with the organelles observed by confocal laser scanning microscopy indicated that late endosomes, lysosomes, endoplasmic reticulum and Golgi apparatus appeared to participate in the intracellular trafficking progression of the micelles. These results suggested that PepT1-targeted polymeric micelles might have a strong potential to greatly promote the oral absorption of poorly water-soluble and absorbed agents.

Oxygen Consumption and Organic Matter Remineralization in Two Subtropical, Eutrophic Coastal Embayments.

There is a strong need to understand sources of organic matter in coastal lagoons because these systems often have long water residence times, are susceptible to eutrophication, and display symptoms such as low-oxygen conditions. We found that integrated dissolved oxygen (DO) consumption in the water column accounted for 67-73% of total DO consumption in two eutrophic coastal lagoons (Baffin Bay and Oso Bay) in the northwestern Gulf of Mexico. The δ13C of particulate organic carbon (δ13CPOC) showed temporal variations that corresponded with hydrological condition changes in Baffin Bay but fewer temporal changes in Oso Bay, whereas the lower δ15NPON values in Baffin Bay indicated more agricultural influence than in Oso Bay, where urban sewage influences dominated. Based on closed-system incubation experiments, water-column respiration in Baffin Bay was driven by the respiration of a combination of phytoplankton, carbon from near-shore and benthic macrophytes, and other allochthonous organic carbon sources depending on hydrological conditions. However, respiration of algal carbon dominated DO consumption in Baffin Bay sediments. In comparison, Oso Bay water-column respiration was largely attributed to the degradation of phytoplankton, the growth of which was sustained by nutrient discharge from wastewater treatment plants in the watershed. In contrast to the water column, seagrass and saltmarsh carbon appeared to be the primary organic carbon source that drove DO consumption in Oso Bay sediments. These observations highlight the complexity of organic carbon sources that contribute to DO consumption in estuaries affected by human activities, especially in systems with long water residence times that can retain both organic matter and nutrients for extended periods of time.

Temporal and spatial fluctuations of groundwater-derived alkalinity fluxes to a semiarid coastal embayment.

We conducted a comprehensive analysis of a variety of geochemical data including total alkalinity (TA), dissolved inorganic carbon (DIC), dissolved organic carbon (DOC), major ions, stable isotopes, and submarine groundwater discharge, to understand biogeochemical and hydrologic processes driving the seasonal to annual estuarine buffering capacity in Nueces Bay, Texas. These measurements, together with statistical analysis and geochemical modeling, show large variability of freshwater influence. TA consumption, common to spring seasons, was mainly driven by CaCO3 precipitation and, to some extent, by aerobic respiration. TA production occurred in some parts of the bay during summer, fall and winter, likely driven by denitrification. CaCO3 dissolution is stimulated by input of undersaturated river waters following significant flooding events. Since consumption and production of TA was not necessarily associated with different salinity zones, SGD, identified to be significant year-round, likely offsets the effects of salinity changes. Net DIC and TA fluxes exceeded dissolved organic carbon flux by an order of magnitude, except for winter 2014 when it was in the same order of magnitude. In addition to generally larger SGD rates when compared to other studies, production of TA (DIC and DOC) in the bottom sediments, as observed in this study, leads to larger fluxes, especially for the driest season (winter 2014), in the mid-bay area (6.27·106µMm-2d-1). Consistently larger inputs occur along the shoreline stations (6.14·106µMm-2d-1) following the flood recession, when compared to mid-bay (1.26·106µMm-2d-1) and are associated with lower SGD following the summer 2015 flooding. This study demonstrates that the carbonate chemistry of estuaries in semiarid areas is affected by non-conservative processes because of seasonal variability of hydroclimatic conditions.

Continental shelves as a variable but increasing global sink for atmospheric carbon dioxide.

It has been speculated that the partial pressure of carbon dioxide (pCO2) in shelf waters may lag the rise in atmospheric CO2. Here, we show that this is the case across many shelf regions, implying a tendency for enhanced shelf uptake of atmospheric CO2. This result is based on analysis of long-term trends in the air-sea pCO2 gradient (ΔpCO2) using a global surface ocean pCO2 database spanning a period of up to 35 years. Using wintertime data only, we find that ΔpCO2 increased in 653 of the 825 0.5° cells for which a trend could be calculated, with 325 of these cells showing a significant increase in excess of +0.5 µatm yr-1 (p < 0.05). Although noisier, the deseasonalized annual data suggest similar results. If this were a global trend, it would support the idea that shelves might have switched from a source to a sink of CO2 during the last century.