Tumor Microenvironment-Responsive Nanocapsule Delivery CRISPR/Cas9 to Reprogram the Immunosuppressive Microenvironment in Hepatoma Carcinoma.

Cancer immunotherapy has demonstrated significant efficacy in various tumors, but its effectiveness in treating Hepatocellular Carcinoma (HCC) remains limited. Therefore, there is an urgent need to identify a new immunotherapy target and develop corresponding intervention strategies. Bioinformatics analysis has revealed that growth differentiation factor 15 (GDF15) is highly expressed in HCC and is closely related to poor prognosis of HCC patients. The previous study revealed that GDF15 can promote immunosuppression in the tumor microenvironment. Therefore, knocking out GDF15 through gene editing could potentially reverse the suppressive tumor immune microenvironment permanently. To deliver the CRISPR/Cas9 system specifically to HCC, nanocapsules (SNC) coated with HCC targeting peptides (SP94) on their surface is utilized. These nanocapsules incorporate disulfide bonds (SNCSS) that release their contents in the tumor microenvironment characterized by high levels of glutathione (GSH). In vivo, the SNCSS target HCC cells, exert a marked inhibitory effect on HCC progression, and promote HCC immunotherapy. Mechanistically, CyTOF analysis showed favorable changes in the immune microenvironment of HCC, immunocytes with killer function increased and immunocytes with inhibitive function decreased. These findings highlight the potential of the CRISPR-Cas9 gene editing system in modulating the immune microenvironment and improving the effectiveness of existing immunotherapy approaches for HCC.

A "Mesh Scaffold" that regulates the mechanical properties and restricts the phase transition-induced volume change of the PNIPAM-based hydrogel for wearable sensors.

Poly(N-isopropylacrylamide) (PNIPAM) is capable of improving the reversibility and responsiveness of flexible electronics. However, its phase transition-induced volume variation and poor adhesiveness remain limitations for expending its applications. Herein, a pressure-sensitive adhesive (PSA), which is a type of mesh scaffold, is constructed inside the network of PNIPAM, providing the hydrogel with a constant volume in response to different temperatures, in situ tunable mechanical properties, and superior adhesiveness. The reversible density of the mesh scaffold adjusts the aggregation state of the hydrogel chains, whereupon it is capable of changing its mechanical modulus from 6.7 kPa to 45.3 kPa. This mechanical mechanism contributes to hydrogel-based flexible devices for multiple applications, especially in pressure-related sensors. The mesh scaffold restricts the phase-transition-induced volume variation, which allows the hydrogel sensor to stably monitor the external pressure at various temperatures. The high adhesion enables the effective interfacial interaction with the skin, avoiding the loss of sensing signals during the detection of human body movements. When it is assembled into an electronic device, it can transmit information and recognize sign language via Morse code. Thus, herein, we report a hydrogel sensor that is promising for pressure detection in temperature-unstable environments, especially for managing the health of patients who require emergency medical care through sign language recognition.

A wave energy driven high-performance self-powered oil spill positioner.

The oil spill positioner is capable of real-time monitoring oil films on the sea surface. However, the lack of high-performance power supply methods greatly restricts the application of oil spill positioner. In this research, we design a high-performance self-powered oil spill positioner based on a soft-contact-triboelectric-nanogenerator (SC-TENG). This device achieves soft-contact by attaching rabbit fur to the rotor, which can effectively reduce frictional resistance, quickly transfer charge to the electrode, and improve the durability of the parts. First, we calculate the highest occupied molecular orbital and the lowest unoccupied molecular orbital of polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF) molecules through first-principles simulations, and compared the ease of electron excitation between the two materials. The results show that the performance of SC-TENG with PVDF as dielectric material is significantly better than that of PTFE. At the same time, this phenomenon has been confirmed by experiments. On the basis of experimental and simulate research on two types of power management circuits, a bridge rectifier circuit with the function of converting alternating current to direct current is selected to realize the self-power supply of the oil spill positioner. Additionally, by optimizing the structure of the SC-TENG and employing a bridge rectifier circuit, the SC-TENG can achieve a maximum open-circuit voltage of 1400 V and a short-circuit current of 3.49µA, which are enough to light up 200 light-emitting diodes and power the oil spill positioner. Finally, we simulate the open-circuit voltage and short-circuit current of the SC-TENG on a six-degree-of-freedom platform and test its durability under real-world ocean wave conditions, all of which show excellent performance. This work develops an efficient wave energy conversion mechanism and successfully realizes the high-performance self-powering of the oil spill positioner, making oil spill monitoring more flexible and reliable.

Diastereoselective Synthesis of Chromeno[3,2-d]isoxazoles via Brønsted Acid Catalyzed Tandem 1,6-Addition/Double Annulations of o-Hydroxyl Propargylic Alcohols.

A Brønsted acid catalyzed tandem process to access densely functionalized chromeno[3,2-d]isoxazoles with good to excellent yields and diastereoselectivities was disclosed. The procedure is proposed to involve a 1,6-conjugate addition/electrophilic addition/double annulations process of alkynyl o-quinone methides (o-AQMs) in situ generated from o-hydroxyl propargylic alcohols with nitrones. Mild conditions, good functional group compatibility, easy scale-up of the reaction, and further product transformation demonstrated its potential application.

Distribution and environmental risk assessment of microplastics in continental shelf sediments in the southern East China Sea: A high-spatial-resolution survey.

We report a high-spatial-resolution study on the distributions, characteristics, and environmental risks of microplastics in surface sediments of the southern East China Sea. Microplastics were omnipresent in the sediments (concentration range: 53.3-246.7; mean: 138.4 particles/kg dry-weight sediment) and enriched in nearshore areas close to urban centers relative to lower offshore concentrations. The microplastics identified were dominated by polyethylene (41.2%) and polyethylene terephthalate (19.9%) in polymer type, fibers (45.8%) and fragments (40.3%) in shape, 0.1-0.5 mm (61.0%) in size, and black (52.0%) in color. The benthic environment experienced low to moderate microplastic pollution, with polyvinylchloride exhibiting the highest ecological risk index. The high-resolution sampling revealed highly diverse polymer types and strongly patchy distributions of microplastic abundance and pollution indices in sediments. Results from this study imply that complex physical, biological, and topographic interactions control the distribution of microplastics and the associated environmental risks in coastal sediments.

Pharmacokinetics, distribution, metabolism, and excretion of body-protective compound 157, a potential drug for treating various wounds, in rats and dogs.

Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t1/2) of prototype BPC157 was less than 30 min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%-19% in rats and 45%-51% in beagle dogs. Using [3H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [3H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.

Occurrence, spatial distribution, source, and ecological risk assessment of organochlorine pesticides in Dongting Lake, China.

The occurrence, distribution, sources, and ecological risks of organochlorine pesticides in Dongting Lake of China were investigated. The average concentrations of organochlorine pesticides (OCPs) in 22 surface water samples and 14 sediment samples were 90.07 ng/L and 80.65 ng/g dw, respectively. Sixteen types of OCPs, dominated by HCHs, DDTs and heptachlor, were detected in the Dongting Lake. The relationships of OCP residues between Dongting Lake and its tributary rivers have been discussed and the hydraulic connections with the Yangtze River and the Three Gorges Dam (TGD) were also considered. Results showed that the shortage of runoff, earlier dry season, and reduction of sediment deposition extremely deteriorated the hydraulic conditions, magnified the water cycle, and restrained the self-purification of OCPs. The ∑OCPs in surface water were concentrated in the inlets of Yangtze River, Lishui River, Zishui River, Yuanshui River, and Xiangjiang River. Moreover, the ∑OCPs in the outlet of the Yangtze River also maintained a high level, indicating that OCPs posed adverse effects on the Yangtze River. Risk assessments of OCPs in the surface water of Dongting Lake were estimated according to available water quality guidelines and health risk assessment models. The results indicated that OCPs in the surface water of Dongting Lake were safe for aquatic organisms and human health. In addition, sediment quality guidelines (SQGs) were also applied to evaluate the potential ecotoxicological risks of OCPs in sediments. The results presented that contaminants of γ-HCH; o,p'-DDD; and dieldrin in sediment had adverse effects on benthic organisms, indicating that fundamental solutions should be proposed to control OCP contamination in Dongting Lake.

An optimized procedure for extraction and identification of microplastics in marine sediment.

Microplastics (MPs) in sediment environments have been widely reported. As the number of samples increases, establishing a reliable and effective method becomes increasingly urgent for the rapid extraction and identification of MPs in sediments. Herein, we proposed a system with continuous density flotation of NaBr-ZnCl2 (mixture of NaBr and ZnCl2) solution for extracting MPs in a sediment sample, combined with micro-Fourier transform infrared (µ-FT-IR) imaging scanning for identification of MPs. The recoveries of MPs were estimated for four different sizes, shapes, and ten different types of polymers. The results indicated NaBr-ZnCl2 solution showed a high recovery rate from 88.33% to 100.00% for extracting these different MPs. The µ-FT-IR imaging scanning allows for the detection of plastic down to the size of 6.25 µm in filed samples, and merely takes about 3 min, which was validated by testing of sediments from Jiaozhou Bay, China and its adjacent estuaries.

Assessing the potential risk and relationship between microplastics and phthalates in surface seawater of a heavily human-impacted metropolitan bay in northern China.

The impacts of microplastics (MPs) and phthalates (PAEs), a class of MP-associated contaminants, on the marine environment are not thoroughly understood despite concern over their adverse effects on humans and ecosystems. Field studies linking MPs and PAEs in seawater have not yet been reported. We investigate for the first time the correlation between MPs contamination and the presence of PAEs in the surface seawater of Jiaozhou Bay (JZB), a semi-enclosed metropolitan bay in northern China heavily impacted by human activity. The abundance of MPs, dominated by polyethylene and polyethylene terephthalate mostly smaller than 2 mm, ranged between 24.44 items/m3 and 180.23 items/m3, with the majority being black and transparent fibers and fragments. Concentrations of PAEs varied from 129.96 ng/L to 921.22 ng/L. Relatively higher abundances of MPs and higher concentrations of PAEs were generally found in areas near riverine inputs and sewage treatment plants. There was a strong correlation between PAEs concentration and MPs abundance, suggesting that they are closely linked. In a risk assessment combining PAEs and MPs, the risk quotients (RQs) indicated that the ecological risk of di-n-butyl phthalate in JZB was relatively high (0.046

Antibacterial effect of S-Porphin sodium photodynamic therapy on Staphylococcus aureus and multiple drug resistance Staphylococcus aureus.

BACKGROUND: Antibacterial photodynamic therapy (aPDT) has been proposed as an alternative strategy to inactivate bacteria. This study was designed to investigate the antibacterial effect of a novel photosensitizer S-Porphin sodium (S-PS) on plankton and biofilm cultures of Staphylococcus aureus (S. aureus) and its multiple drug resistance strain S. aureus (MDR S. aureus). METHODS: The plate counting method was used to evaluate the antimicrobial effect of S-PS-aPDT. The bacterial viability was detected by SYTO9/PI. The intracellular reactive oxygen species (ROS) generation was estimated by electron spin resonance spectroscopy and flow cytometry. The destruction of bacteria and biofilm was observed by scanning electron microscope (SEM) and atomic force microscope (AFM), respectively. RESULTS: The aPDT induced antibacterial effect in S. aureus and MDR S. aureus was S-PS concentration- and light dose-dependent. S. aureus exhibited much higher sensitivity to aPDT than MDR S. aureus, regarding to cell killing, ROS level, as well as morphological damages under AFM observation. When pretreated with the efflux pump inhibitors (EPIs), the intracellular uptake of S-PS in MDR S. aureus increased and the coupled aPDT produced significantly enhanced antibacterial efficiency. CONCLUSION: S-PS-aPDT exhibited excellent bactericidal activity in plankton and biofilms. S-PS might be a good candidate for using in PDT anti-bacterial field. The introduction of EPIs could effectively improve the killing effect of MDR S. aureus.

Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.

Calpains are intracellular cysteine proteases that catalyze the cleavage of target proteins in response to Ca(2+) signaling. When Ca(2+) homeostasis is disrupted, calpain overactivation causes unregulated proteolysis, which can contribute to diseases such as postischemic injury and cataract formation. Potent calpain inhibitors exist, but of these many cross-react with other cysteine proteases and will need modification to specifically target calpain. Here, we present crystal structures of rat calpain 1 protease core (muI-II) bound to two alpha-ketoamide-based calpain inhibitors containing adenyl and piperazyl primed-side extensions. An unexpected aromatic-stacking interaction is observed between the primed-side adenine moiety and the Trp298 side chain. This interaction increased the potency of the inhibitor toward muI-II and heterodimeric m-calpain. Moreover, stacking orients the adenine such that it can be used as a scaffold for designing novel primed-side address regions, which could be incorporated into future inhibitors to enhance their calpain specificity.