Engineering Logic DNA Nanoprobes on Live Cell Membranes for Simultaneously Monitoring Extracellular pH and Precise Drug Delivery.

It remains a challenge to use a single probe to simultaneously detect extracellular pH fluctuations and specifically recognize cancer cells for precise drug delivery. Here, we engineered a tetrahedral framework nucleic acid-based logic nanoprobe (isgc8-tFNA) on live cell membranes for simultaneously monitoring extracellular pH and targeted drug delivery. Isgc8-tFNA was anchored stably on the cell surface through three cholesterol molecules inserting into the bilayer of the cell membrane. Once responding to the acidic tumor microenvironment, isgc8-tFNA formed an i-motif structure, leading to turn-on FRET signals for monitoring changes of extracellular pH. The nanoprobe exhibited a narrow pH-response window and excellent reversibility. Moreover, the nanoprobe could execute logic identification on the cell surface for precise drug delivery. Only if both in the acidic microenvironment and aptamer-targeting marker are present on the cell surface, the sgc8-ASO-chimera strand, carrying an antisense oligonucleotide drug, was released from the nanoprobe and entered into targeted cancer cells for gene silence. Additionally, the in situ drug release facilitated the uptake of drugs mediated by the interaction between sgc8 aptamer and membrane proteins, resulting in enhanced inhibition of cancer cell migration and proliferation. This logic nanoprobe will provide inspiration for designing smart devices for diagnosis of pH-related diseases and targeted drug delivery.

Kindlin supports platelet integrin αIIbß3 activation by interacting with paxillin.

Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbß3 activation. An exposed loop in the N-terminal F0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbß3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbß3 activation and in vivo platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbß3 activation, which might be beneficial for developing safer anti-thrombotic therapies.

Fibril aggregates formed by a glatiramer-mimicking random copolymer of amino acids.

Amyloid formation is now considered a universal and intrinsic property of all proteins, irrespective of their sequences. Therefore, it is interesting to see whether random copolymers of amino acids can also form amyloid aggregates. Here we use a copolymer of 4 amino acids, mimicking the clinically used drug Glatiramer, and demonstrate that it does form amyloid-like fibrils in the aqueous solution despite its random sequence structure. The fibrillar aggregates show an alanine-rich ß-sheet secondary structure, proving the high tolerance of amyloid aggregates to the sequence irregularity in poly(amino acid)s, and suggesting the potential application of random copolymers as amyloid materials.

Recent Advances in Nickel Catalysts with Industrial Exploitability for Copolymerization of Ethylene with Polar Monomers.

The direct copolymerization of ethylene with polar monomers to produce functional polyolefins continues to be highly appealing due to its simple operation process and controllable product microstructure. Low-cost nickel catalysts have been extensively utilized in academia for the synthesis of polar polyethylenes. However, the development of high-temperature copolymerization catalysts suitable for industrial production conditions remains a significant challenge. Classified by the resultant copolymers, this review provides a comprehensive summary of the research progress in nickel complex catalyzed ethylene-polar monomer copolymerization at elevated temperatures in the past five years. The polymerization results of ethylene-methyl acrylate copolymers, ethylene-tert-butyl acrylate copolymers, ethylene-other fundamental polar monomer copolymers, and ethylene-special polar monomer copolymers are thoroughly summarized. The involved nickel catalysts include the phosphine-phenolate type, bisphosphine-monoxide type, phosphine-carbonyl type, phosphine-benzenamine type, and the phosphine-enolate type. The effective modulation of catalytic activity, molecular weight, molecular weight distribution, melting point, and polar monomer incorporation ratio by these catalysts is concluded and discussed. It reveals that the optimization of the catalyst system is mainly achieved through the methods of catalyst structure rational design, extra additive introduction, and single-site catalyst heterogenization. As a result, some outstanding catalysts are capable of producing polar polyethylenes that closely resemble commercial products. To achieve industrialization, it is essential to further emphasize the fundamental science of high-temperature copolymerization systems and the application performance of resultant polar polyethylenes.

Recent Advancements in Mechanistic Studies of Palladium- and Nickel-Catalyzed Ethylene Copolymerization with Polar Monomers.

The introduction of polar functional groups into polyolefin chain structures creates opportunities to enhance specific properties, such as adhesion, dyeability, printability, compatibility, thermal stability, and electrical conductivity, which widen the range of potential applications for these modified materials. Transition metal catalysts, especially late transition metals, have proven to be highly effective in copolymerization processes due to their reduced Lewis acidity and electrophilicity. However, when compared to the significant progress and summary of synthetic methods, there is a distinct lack of a comprehensive summary of mechanistic studies pertaining to the catalytic systems involved in ethylene copolymerization catalyzed by palladium and nickel catalysts. In this review, we have provided a comprehensive summary of the latest developments in mechanistic studies of ethylene copolymerization with polar monomers catalyzed by late-transition-metal complexes. Experimental and computational methods were employed to conduct a detailed investigation of these organic and organometallic systems. It is mainly focused on ligand substitution, changes in binding modes, ethylene/polar monomer insertion, chelate opening, and ß-H elimination. Factors that control the catalytic activity, molecular weight, comonomer incorporation ratios, and branch content are analyzed, these include steric repulsions between ligands and monomers, electronic effects arising from both ligands and monomers, and so on.

Observation and Analysis of Clinical Efficacy of Zhuang Medicine Lotus Acupuncture Cupping Stasis Therapy on Patients with Postherpetic Neuralgia.

OBJECTIVE: To explore the clinical efficacy of Zhuang Medicine Lotus Acupuncture Cupping Stasis Therapy on patients with postherpetic neuralgia (PHN) and its action mechanism. METHODS: 36 patients are randomly divided into Lotus Acupuncture Cupping Stasis Therapy group, pure cupping group and gabapentin group, with a total of five observation points for the first, fifth, tenth, fifteenth, and twentieth sessions of therapy (one session every three days). At each observation point, the venous blood of the patients is taken, and the contents of and changes in WNT3a, Frizzled8, ß-catenin, IL-18, TNF-α, NR2B, NK-1 and SP are tested by ELISA, RT-PCR and WesternBlot, respectively. The VAS scores and safety of the patients in the three groups are compared. RESULTS: With increased time spent in therapy, the VAS scores of patients in each group decreased gradually and there was a significant reduction in pain in patients in the Lotus Acupuncture Cupping Stasis Therapy group compared to the gabapentin and pure cupping groups (P<0.05). The levels of IL-18, TNF-α, NK-1, SP, WNT3a, Frizzled 8 and ß-catenin in the serum of all patients experienced a constant decline over time (P<0.05); the levels of the aforesaid factors in the serum of patients in the Lotus Acupuncture Cupping Stasis Therapy group dropped remarkably after the tenth session of therapy compared to those in gabapentin and pure cupping groups (P<0.05). CONCLUSIONS: Zhuang Medicine Lotus Acupuncture Cupping Stasis Therapy can significantly reduce the pain of PHN patients, with a good therapeutic effect, and it is worthy of clinical use.

Recent Advances in the Copolymerization of Ethylene with Polar Comonomers by Nickel Catalysts.

The less-expensive and earth-abundant nickel catalyst is highly promising in the copolymerization of ethylene with polar monomers and has thus attracted increasing attention in both industry and academia. Herein, we have summarized the recent advancements made in the state-of-the-art nickel catalysts with different types of ligands for ethylene copolymerization and how these modifications influence the catalyst performance, as well as new polymerization modulation strategies. With regard to α-diimine, salicylaldimine/ketoiminato, phosphino-phenolate, phosphine-sulfonate, bisphospnine monoxide, N-heterocyclic carbene and other unclassified chelates, the properties of each catalyst and fine modulation of key copolymerization parameters (activity, molecular weight, comonomer incorporation rate, etc.) are revealed in detail. Despite significant achievements, many opportunities and possibilities are yet to be fully addressed, and a brief outlook on the future development and long-standing challenges is provided.

Precipitation Polymerization: A Powerful Tool for Preparation of Uniform Polymer Particles.

Precipitation polymerization (PP) is a powerful tool to prepare various types of uniform polymer particles owing to its outstanding advantages of easy operation and the absence of any surfactant. Several PP approaches have been developed up to now, including traditional thermo-induced precipitation polymerization (TRPP), distillation precipitation polymerization (DPP), reflux precipitation polymerization (RPP), photoinduced precipitation polymerization (PPP), solvothermal precipitation polymerization (SPP), controlled/''living'' radical precipitation polymerization (CRPP) and self-stabilized precipitation polymerization (2SPP). In this review, a general introduction to the categories, mechanisms, and applications of precipitation polymerization and the recent developments are presented, proving that PP has great potential to become one of the most attractive polymerization techniques in materials science and bio-medical areas.

Effects of HIF-1α, hepcidin and PTH on RankL in patients with chronic kidney disease in different stages.

OBJECTIVE: To investigate the effects of hypoxia-inducible factor-1α (HIF-1α), hepcidin, and parathyroid hormone (PTH) on the serum nuclear factor κB and receptor activating factor ligand (RankL) in patients with chronic kidney disease (CKD) stages 3-5. METHODS: A total of 90 patients admitted to our hospital's Department of Nephrology from March 2018 to December 2019 were randomly selected as the subjects (30 patients with CKD3, CKD4, and CKD5 each). A total of 30 healthy volunteers receiving a physical examination in our hospital during the same period were selected for the control group. Then, the participants' HIF-1α, hepcidin, and RankL levels were detected by double-antibody sandwiched enzyme-linked immunosorbent assay. The serum creatinine, serum iron, hemoglobin, and phosphorus (P3+) levels were determined by BeckMAN-c800 automatic biochemical analysis. The glomerular filtration rate (eGFR) was calculated by the CKD-EPI formula. RESULTS: (1) The levels of HIF-1α, RankL, hepcidin, and PTH were all elevated, and the serum ferritin and P3+ were elevated in each stage; (2) Linear correlation analysis: The HIF-1α and hepcidin showed a higher correlation with RankL in CKD3 and CKD4(CKD3: The correlation coefficient r = 0.558 between HIF-1α and RankL, and r = 0.604 between HEpcidin and RankL; CKD4: Correlation coefficient r = 0.840 between HIF-1α and RankL, and r = 0.753 between HEpcidin and RankL), while the PTH showed a higher correlation with RankL in CKD5 (correlation index r = 0.631). Multiple linear stepwise regression analysis: RankL was independently correlated with HIF-1α, hepcidin, and PTH. Regression coefficient B of HIF-1α was the highest in both CKD3 and CKD4. The coefficient B value of PTH in CKD5 was 3.971; HIF-1α and hepcidin were not included in the regression equation. CONCLUSION: The levels of RankL in both CKD3 and CKD4 were increased and mainly affected by HIF-1α, followed by hepcidin. Moreover, HIF-1α and PTH had a combined effect on the RankL level in CKD5, and PTH was the main influencing factor.

Evaluation of an in situ chemically crosslinked hydrogel as a long-term vitreous substitute material.

Currently there is no material that can be used as a long-term vitreous substitute, and this remains an unmet clinical need in ophthalmology. In this study, we developed an injectable, in situ chemically crosslinked hydrogel system and evaluated it in a rabbit model. The system consisted of two components, both based on multi-functional poly(ethylene glycol) (PEG) but with complementarily reactive end groups of thiol and active vinyl groups, respectively. The two components are mixed and injected as a solution mixture, react in vivo via the Michael addition route and form a chemically crosslinked hydrogel in situ. The linkages between the end groups and the backbone PEG chains are specially designed to ensure that the final network structure is hydrolysis-resistant. In the rabbit study and with an optimized operation protocol, we demonstrated that the hydrogel indeed formed in situ after injection, and remained transparent and stable during the study period of 9 months without significant adverse reactions. In addition, the hydrogel formed in situ showed rheological properties very similar to the natural vitreous. Therefore, our study demonstrated that this in situ chemically crosslinked PEG gel system is suitable as a potential long-term vitreous substitute.