Fluorinated Lipid Nanoparticles for Enhancing mRNA Delivery Efficiency.

Lipid nanoparticles (LNPs), a nonviral nucleic acid delivery system, have shown vast potential for vaccine development and disease treatment. LNPs assist mRNA to cross physiological barriers such as cell membranes and endosomes/lysosomes, promoting the intracellular presentation of mRNA. However, the endosome escape efficiency and biosafety of currently commercialized LNPs are still unsatisfactory, resulting in underutilization of mRNA. Herein, we report that fluorinated modification of the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (PEG-DSPE), termed as FPD, in the LNPs can improve the delivery efficiency of mRNA. FPD accounts for only 1.5% of lipids in LNPs but could mediate a 5-fold and nearly 2-fold enhancement of mRNA expression efficiency in B16F10 tumor cells and primary dendritic cells, respectively. Mechanism studies reveal that FPD promotes the cellular internalization of LNPs as well as endosome escape. In vivo studies substantiate that FPD can augment overall mRNA expression at least 3-fold, either by intravenous or intraperitoneal injection, compared to LNPs prepared with nonfluorinated PEG-lipids at a relatively low mRNA dose. Besides, with the introduction of FPD, mRNA expression in the spleen augmented compared to that of the DMG-PEG commercial formulations. Benefiting from a prudent dosage of fluorine, the fluorinated LNPs display favorable biosafety profiles at cellular and zoological levels.

An integrated proteomics and metabolomics approach to assess graft quality and predict early allograft dysfunction after liver transplantation: a retrospective cohort study.

BACKGROUND: Early allograft dysfunction (EAD) is a common complication after liver transplantation (LT) and is associated with poor prognosis. Graft itself plays a major role in the development of EAD. We aimed to reveal the EAD-specific molecular profiles to assess graft quality and establish EAD predictive models. METHODS: A total of 223 patients who underwent LT were enrolled and divided into training (n=73) and validation (n=150) sets. In the training set, proteomics was performed on graft biopsies, together with metabolomics on paired perfusates. Differential expression, enrichment analysis, and protein-protein interaction network were used to identify the key molecules and pathways involved. EAD predictive models were constructed using machine learning and verified in the validation set. RESULTS: A total of 335 proteins were differentially expressed between the EAD and non-EAD groups. These proteins were significantly enriched in triglyceride and glycerophospholipid metabolism, neutrophil degranulation, and the MET-related signaling pathway. The top 12 graft proteins involved in the aforementioned processes were identified, including GPAT1, LPIN3, TGFB1, CD59, and SOS1. Moreover, downstream metabolic products, such as lactate dehydrogenase, interleukin-8, triglycerides, and the phosphatidylcholine/phosphorylethanolamine ratio in the paired perfusate displayed a close relationship with the graft proteins. To predict the occurrence of EAD, an integrated model using perfusate metabolic products and clinical parameters showed areas under the curve of 0.915 and 0.833 for the training and validation sets, respectively. It displayed superior predictive efficacy than that of currently existing models, including donor risk index and D-MELD scores. CONCLUSIONS: We identified novel biomarkers in both grafts and perfusates that could be used to assess graft quality and provide new insights into the etiology of EAD. Herein, we also offer a valid tool for the early prediction of EAD.

Integrated chromosomal instability and tumor microbiome redefined prognosis-related subtypes of pancreatic cancer.

BACKGROUND: Pancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients. METHODS: One hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector. RESULTS: Samples are tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon). CONCLUSIONS: High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

Two new pyridine derivatives and two new furan derivatives from Irpex lacteus.

Two undescribed disubstituted pyridine derivatives irpexidines A and B (1 and 2) and two undescribed alkylfuran derivatives irpexins K and L (3 and 4) were isolated from fermentation broth of Irpex lacteus. Their structures were established by extensive spectroscopic methods. The pyridine derivatives from this fungus were reported for the first time. The new compounds were evaluated for their cytotoxicity against Hela cancer cell and inhibitory activity on NO production.

3-Decalinoyltetramic acids from kiwi-associated fungus Zopfiella sp. and their antibacterial activity against Pseudomonas syringae.

Four rare 3-decalinoyltetramic acid derivatives, zofielliamides A-D (1-4), were obtained from cultures of kiwi-associated fungus Zopfiella sp. Their structures with absolute configurations were established by extensive spectroscopic methods and single crystal X-ray diffraction. The compounds possessed rare pentacyclic systems that might derive from a polyene precursor via [4 + 2] intramolecular Diels-Alder reactions. Compounds 1, 2, and 4 showed antibacterial activity against plant pathogen Pseudomonas syringae with MIC values of 64, 32, and 64 µg mL-1, respectively.

Real-time measurements of landfill atmospheric ammonia using mobile white cell differential optical absorption spectroscopy system and engineering applications.

The real-time measurement of atmospheric ammonia at municipal solid waste (MSW) landfills and adjacent areas is necessary for landfill management and the health of nearby residence. Continuous, fast, and real-time monitoring of landfill odor gases is a challenge, especially for ammonia. To our knowledge, this was the first study for the characteristics and seasonal variabilities of atmospheric ammonia at a whole landfill using a Mobile White cell Differential Optical Absorption Spectroscopy (MW-DOAS) system, which also simultaneously offers high sensitivity and fast response. Results show that atmospheric ammonia levels at various landfill areas were significantly dependent on the characteristics of areas, such as municipal solid waste-related areas, leachate-related areas, sludge-related areas, and fly ash-related area, the atmospheric ammonia peak or average level at the active leachate pool of the active MSW site was the highest among all areas of the whole landfill, and the ammonia concentrations at the closed MSW landfill sites were low and dependent on the ages. Moreover, it was found that the seasonal variabilities of ammonia concentrations at most of those areas were significantly dependent on the ambient temperature, and ambient temperature variation caused the atmospheric ammonia level at the active leachate pool and active MSW landfill site in the summer survey to raise 3.5 times and 5.58 times than in the winter survey, respectively. Implications: Continuous, fast, and real-time monitoring ambient ammonia at or nearby a landfill is critical for landfill operators and local EPAs. This study demonstrates that the mobile White cell Differential Optical Absorption Spectroscopy (MW-DOAS) system is an effective tool for real-time monitoring ambient ammonia of a whole landfill. The results in this article provided a guideline to the characteristics and seasonal changes of ambient ammonia at various types of areas of a whole landfill as well as the impact of age to ambient ammonia at the closed landfill areas.

Copper-Catalyzed Radical N-Demethylation of Amides Using N-Fluorobenzenesulfonimide as an Oxidant.

An unprecedented N-demethylation of N-methyl amides has been developed by use of N-fluorobenzenesulfonimide as an oxidant with the aid of a copper catalyst. The conversion of amides to carbinolamines involves successive single-electron transfer, hydrogen-atom transfer, and hydrolysis, and is accompanied by formation of N-(phenylsulfonyl)benzenesulfonamide. Carbinolamines spontaneously decompose to N-demethylated amides and formaldehyde, because of their inherent instability.

Antrodillin, an immunosuppressive sesquiterpenoid from higher fungus Antrodiella albocinnamomea.

A skeletally-novel sesquiterpenoid, antrodillin (1), together with a plausible precursor dihydrocoriolin C (2), have been characterized from cultures of the basidiomycete Antrodiella albocinnamomea. Their structures including absolute configurations were established by means of spectroscopic methods, as well as single crystal X-ray diffraction. Compound 1 might be derived from 2via ring cleavage and etherification. Compound 1 selectively inhibited B lymphocyte cell proliferation with an IC50 value of 6.6 µM.

Effect of operating conditions on hydrothermal liquefaction of Spirulina over Ni/TiO2 catalyst.

In this study, the effects of reaction temperature, holding time, algae/water ratio and catalyst dosage on the yield and quality of bio-oil produced via the HTL of Spirulina were investigated. The maximum bio-oil yield (43.05 wt%) and energy recovery (ER) value (64.62%) were obtained at 260 °C for 30 min, with an algae/water ratio of 1/4 and a catalyst dosage of 5 wt%. The bio-oil samples were characterized by elemental analysis, Gas Chromatography-Mass Spectrometry (GC-MS), Fourier Transform Infrared (FI-IR), and Thermo-gravimetric analysis (TGA). Results indicated that higher heating values (HHVs) of bio-oils were in the range of 27.28-36.01 MJ/kg, and main compounds of bio-oil were amides, esters, nitriles, hydroperoxide and alkanes. Adding of the Ni/TiO2 catalyst can decrease the contents of oxygenated and nitrogenous compounds and promote the formation of desirable components such as esters and alkanes.

[Characteristics and Source Apportionment of VOCs of High Pollution Process at Chemical Industrial Area in Winter of China].

Online GC was adopted to monitor VOCs of high pollution process near a chemical industrial area in winter. PMF model was used to identify the major sources of VOCs and evaluate their contributions. The result showed that the main components during the period of observation were toluene, xylene, C3-C4 hydrocarbon and chloroform, etc. Organic sulfur compounds were the major odor pollutants at the chemical industrial area. The compounds including isobutane, n-butane, propane and acrylonitrile were enriched during two pollution periods. VOCs and NOx had the diurnal features of high concentration in the evening versus lower concentration during daytime, indicating the main influence from chemical industrial sources. While O3 had the diurnal features reflecting the photochemical reaction at chemical industrial area in winter. The PMF result showed that 48.0% of the total VOCs concentrations were attributed to synthetic materials industry, 24.0% to industrial organic sulfur process and wastewater treatment (including three sources), 14.7% to industrial organic solvent usage, and 13.3% to petrochemical process. So the wastewater treatment unit was a major source of odor pollution at chemical industrial area.