Assessment of rare earth elements variations in five water systems in Beijing: Distribution, geochemical features, and fractionation patterns.

This study investigates the distribution of rare earth elements (REEs) within the Beijing water system, specifically examining the Yongding, Chaobai, Beiyun, Jiyun, and Daqing rivers. Results indicate that the Beiyun River exhibits the highest REE concentrations, ranging from 35.95 to 59.78 µg/mL, while the Daqing River shows the lowest concentrations, ranging from 15.79 to 17.48 µg/mL. LREEs (La to Nd) predominate with a total concentration of 23.501 µg/mL, leading to a notable LREE/HREE ratio of 7.901. Positive Ce anomalies (0.70-1.11) and strong positive Eu anomalies (1.38-2.49) were observed. The study suggests that the Beijing water system's REEs may originate from geological and anthropogenic sources, such as mining and industrial activities in neighboring regions, including Inner Mongolia. These findings underscore the importance of ongoing monitoring and effective water management strategies to address REE-related environmental concerns.

A compound reflects the level of homocysteine based on Rhodamine B and its ability to respond to homocysteine in the plasma of diabetic patients.

BACKGROUND: The level of homocysteine (Hcy) is significantly elevated in the plasma of patients with diabetes. The increased plasma Hcy level is positively correlated with the severity of the disease and is one of the important causes of diabetic complications. METHODS: We designed and synthesized a compound could reflect the level of Hcy based on rhodamine B, and the structure was verified by 1H-NMR and EI-HRMS. Then, the linearity, repeatability, selectivity, and cellar toxicity, the effects of the fluid viscosity and pH of compound on Hcy were measured; meanwhile, the response of Hcy level in the plasma of diabetic patients was detected. RESULTS: This is a novel compound that has never been reported. The compound showed a satisfactory linear range and repeatability at the viscosity and pH of physiological fluid. In addition, the compound was capable of evading the interference from other amino acids and metal ions, and it exhibited high selectivity toward Hcy. CONCLUSION: The compound showed increased responsiveness to plasma Hcy in patients with diabetes in comparison with healthy individuals and effectively reflected plasma Hcy levels in healthy individuals and diabetic patients. Therefore, the compound is expected to be used in the diagnosis of diabetes mellitus.

Design, synthesis and evaluation of anti-CD38 antibody drug conjugate based on Daratumumab and maytansinoid.

Daratumumab, an FDA approved antibody drug, displays specific targeting ability to abnormal white blood cells overexpressing CD38 and provides efficacious therapy for multiple myeloma. Here, in order to achieve enhanced remission of multiple myeloma, we designed Dara-DM4, antibody drug conjugates (ADCs) by conjugating Daratumumab and DM4 via a disulfide linker. Dara-DM4 showed significantly higher cellular uptake and inhibitory efficacy on MM1S cells that overexpressing CD38 with an IC50 of 0.88 µg/mL post 72 hr treatment. These results support a promising ADCs strategy for multiple myeloma treatment.

GlcNAc Conjugated Atorvastatin with Enhanced Water Solubility and Cellular Internalization.

Targeting ligands facilitate cell specific drug delivery and improve pharmaceutical properties. Herein, we designed two ligand drug conjugates by conjugating GlcNAc (N-acetylglucosamine) with atorvastatin. These two conjugates, termed G-AT and G-K-AT, exhibited enhanced water solubility and cellular uptake. Moreover, both G-AT and G-K-AT were able to release atorvastatin and consequently achieve significant inhibition against 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase.

Design, synthesis and evaluation of anti-CD123 antibody drug conjugates.

Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.

FXR and liver carcinogenesis.

Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer.

Increasing the efficiency of gene editing with CRISPR-Cas9 via concurrent expression of the Beta protein.

Escherichia coli has emerged as an important host for the production of biopharmaceuticals or other industrially relevant molecules. An efficient gene editing tool is indispensable for ensuring high production levels and optimal release of target products. However, in Escherichia coli, the CRISPR-Cas9 system has been shown to achieve gene modifications with relatively low frequency. Large-scale PCR screening is required, hindering the identification of positive clones. The beta protein, which weakly binds to single-stranded DNA but tightly associates with complementary strand annealing products, offers a promising solution to this issue. In the present study, we describe a targeted and continuous gene editing strategy for the Escherichia coli genome. This strategy involves the coexpression of the beta protein alongside the CRISPR-Cas9 system, enabling a variety of genome modifications such as gene deletion and insertion with an efficiency exceeding 80 %. The integrity of beta proteins is essential for the CRISPR-Cas9/Beta-based gene editing system. In this work, the deletion of either the N- or C-terminal domain significantly impaired system efficiency. Overall, our findings established the CRISPR-Cas9/Beta system as a suitable gene editing tool for various applications in Escherichia coli.

Photovoltaic nanocells for high-performance large-scale-integrated organic phototransistors.

A high-performance large-scale-integrated organic phototransistor needs a semiconductor layer that maintains its photoelectric conversion ability well during high-resolution pixelization. However, lacking a precise design for the nanoscale structure, a trade-off between photoelectric performance and device miniaturization greatly limits the success in commercial application. Here we demonstrate a photovoltaic-nanocell enhancement strategy, which overcomes the trade-off and enables high-performance organic phototransistors at a level beyond large-scale integration. Embedding a core-shell photovoltaic nanocell based on perovskite quantum dots in a photocrosslinkable organic semiconductor, ultralarge-scale-integrated (>221 units) imaging chips are manufactured using photolithography. 27 million pixels are interconnected and the pixel density is 3.1 × 106 units cm-2, at least two orders of magnitude higher than in existing organic imaging chips and equivalent to the latest commercial full-frame complementary metal-oxide-semiconductor camera chips. The embedded photovoltaic nanocells induce an in situ photogating modulation and enable photoresponsivity and detectivity of 6.8 × 106 A W-1 and 1.1 × 1013 Jones (at 1 Hz), respectively, achieving the highest values of organic imaging chips at large-scale or higher integration. In addition, a very-large-scale-integrated (>216 units) stretchable biomimetic retina based on photovoltaic nanocells is manufactured for neuromorphic imaging recognition with not only resolution but also photoresponsivity and power consumption approaching those of the biological counterpart.

Sterically polymer-based liposomal complexes with dual-shell structure for enhancing the siRNA delivery.

The sterically polymer-based liposomal complexes (SPLexes) were formed by cationic polymeric liposomes and pH-sensitive diblock copolymer were studied for their capabilities in improving the stability with high efficiency of siRNA delivery. The SPLexes were formed a dual-shelled structure and uniform size distribution. The PEGylated outer shell could mitigate the phagocytosis and reduce the cytotoxicity. Moreover, the folated SPLexes improved 42.9× accumulation in vitro and 1.7× tumor uptake in vivo in contrast with nonfolated SPLexes. The protonated copolymer at low pH would improve the siRNA released into cytoplasm following SPLexes fusion with the endo/lysosome membrane and inhibited the protein expression to 75.6 ± 4.5% efficiently. Results of this study significantly contribute to efforts to develop lipoplexes based siRNA delivery systems.

Data-Driven Technology Roadmaps to Identify Potential Technology Opportunities for Hyperuricemia Drugs.

Hyperuricemia is a metabolic disease with an increasing incidence in recent years. It is critical to identify potential technology opportunities for hyperuricemia drugs to assist drug innovation. A technology roadmap (TRM) can efficiently integrate data analysis tools to track recent technology trends and identify potential technology opportunities. Therefore, this paper proposes a systematic data-driven TRM approach to identify potential technology opportunities for hyperuricemia drugs. This data-driven TRM includes the following three aspects: layer mapping, content mapping and opportunity finding. First we deal with layer mapping.. The BERT model is used to map the collected literature, patents and commercial hyperuricemia drugs data into the technology layer and market layer in TRM. The SAO model is then used to analyze the semantics of technology and market layer for hyperuricemia drugs. We then deal with content mapping. The BTM model is used to identify the core SAO component topics of hyperuricemia in technology and market dimensions. Finally, we consider opportunity finding. The link prediction model is used to identify potential technological opportunities for hyperuricemia drugs. This data-driven TRM effectively identifies potential technology opportunities for hyperuricemia drugs and suggests pathways to realize these opportunities. The results indicate that resurrecting the pseudogene of human uric acid oxidase and reducing the toxicity of small molecule drugs will be potential opportunities for hyperuricemia drugs. Based on the identified potential opportunities, comparing the DNA sequences from different sources and discovering the critical amino acid site that affects enzyme activity will be helpful in realizing these opportunities. Therefore, this research provides an attractive option analysis technology opportunity for hyperuricemia drugs.

A variety of simple and ultra-low-cost methods preparing SLiCE extracts and their application to DNA cloning.

Cell lysates from a laboratory strain of Escherichia coli can be exploited for seamless DNA cloning in vitro, which is named the seamless ligation cloning extract (SLiCE) cloning method. The SLiCE method can incorporate DNA fragments into a vector to achieve conventional DNA cloning and is more cost-effective than commercially seamless DNA cloning kits. In this study, we found that the SLiCE extracts could easily be prepared with different methods, such as 3% Triton X-100 lysis buffer, 3% SDS lysis buffer, or freeze-thaw cycles. At high E. coli transformation efficiency, the SLiCE extracts prepared using different simple and ultra-low cost methods did not affect the DNA cloning efficiency. These results further revealed that the SLiCE cloning method can be efficiently used for seamless DNA cloning in vitro.

Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.

Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy. In this study, we generated novel lipid nanoparticles (LNPs) encapsulated with mRNAs encoding cytokines including IL-12, IL-27 and GM-CSF, and tested their anti-tumor activity. We first synthesized ionizable lipid materials containing di-amino groups with various head groups (DALs). The novel DAL4-LNP effectively delivered different mRNAs in vitro to tumor cells and in vivo to tumors. Intratumoral injection of DAL4-LNP loaded with IL-12 mRNA was most potent in inhibiting B16F10 melanoma tumor growth compared to IL-27 or GM-CSF mRNAs in monotherapy. Furthermore, intratumoral injection of dual DAL4-LNP-IL-12 mRNA and IL-27 mRNA showed a synergistic effect in suppressing tumor growth without causing systematic toxicity. Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8+ T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for cancer.

Preparation of pyrrolidinyl diglycolamide bonded silica particles and its rare earth separation properties.

The separation of rare earth elements by solid phase containing diglycolamide-type ligands is a hot topic. In this study, 2-[2-oxo-2-(1-pyrrolidinyl)ethoxy]acetic acid (PYRDGA) was synthesized and attached to the silica. The binding strength of SiO2@PYRDGA for rare earths showed a single increasing trend with the radius of rare earth atoms. IR and XPS spectra demonstrated that carbonyl oxygen and ether bond oxygen are binding sites for rare earth ions. SiO2@PYRDGA was used for the chromatographic separation of REEs, and the primary separation of 16 REEs was achieved at pH = 2.0 using HNO3 solution as the eluent, and La, Ce, Pr, Nd, Sm, and Eu reached the baseline separation level.

Nanomaterials-Mediated Co-Stimulation of Toll-Like Receptors and CD40 for Antitumor Immunity.

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.

Construction of Messenger RNA (mRNA) Probes Delivered By Lipid Nanoparticles to Visualize Intracellular Protein Expression and Localization at Organelles.

Organelles are specialized compartments, where various proteins reside and play crucial roles to maintain essential cellular structures and functions in mammalian cells. A comprehensive understanding of protein expressions and subsequent localizations at each organelle is of great benefit to the development of organelle-based therapies. Herein, a set of single or dual organelle labeling messenger RNAs (SOLAR or DOLAR) is designed as novel imaging probes, which encode fluorescent proteins with various organelle localization signals. These mRNA probes enable to visualize the protein localizations at different organelles and investigate their trafficking from ribosomal machinery to specific organelles. According to the in vitro results, SOLAR probes show organelle targeting capabilities consistent with the design. Moreover, DOLAR probes with different linkers display distinct targeting properties depending on different organelle localization signals. Additionally, these mRNA probes also exhibit organelle labeling ability in vivo when delivered by lipid nanoparticles (LNPs). Therefore, these mRNA-based probes provide a unique tool to study cell organelles and may facilitate the design of organelle-based therapies.

Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy.

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.

Piezo1 initiates platelet hyperreactivity and accelerates thrombosis in hypertension.

BACKGROUND: Thrombosis is the pathological basis of cardiovascular and cerebrovascular diseases, which seriously threaten human life and health. Among them, nearly half of cardiovascular disease patients suffer from severe hypertension complications. Hypertension is thought to cause abnormal platelet activation and increases the risk of thrombosis, but the related mechanism is still vague. OBJECTIVES: This study hypothesized that the abnormal hemodynamics of blood under hypertension might affect platelet function and accelerate thrombosis by activating mechanoreceptor Piezo1. METHODS: To assess the activation effect of hypertension on mechanoreceptor Piezo1, we injected Piezo1 agonist Yoda1 and antagonist GsMTx-4 through the tail vein, then examined the platelet activation status and thrombosis. RESULTS: Our results displayed that antagonist GsMTx-4 effectively inhibited calcium influx caused by hypertension and agonist Yoda1. Antithrombotic studies proved that the inhibition of Piezo1 effectively inhibited arterial thrombosis and reduced the infarct size of stroke in hypertensive mice. CONCLUSIONS: Our study explains the activation of mechanoreceptor Piezo1 under hypertension is the key to abnormal platelet activation and thrombosis while providing novel platelet intervention strategies to prevent thrombosis.

Vitamin B12 Attenuates Acute Pancreatitis by Suppressing Oxidative Stress and Improving Mitochondria Dysfunction via CBS/SIRT1 Pathway.

Acute pancreatitis is an inflammatory disorder of the pancreas associated with substantial morbidity and mortality, which is characterized by a rapid depletion of glutathione (GSH). Cysthionine-ß-synthase (CBS) is a key coenzyme in GSH synthesis, and its deficiency is related to a variety of clinical diseases. However, whether CBS is involved in the pathogenesis of acute pancreatitis remains unclear. First, we found that CBS was downregulated in both in vivo and in vitro AP models. The pancreatic damage and acinar cell necrosis related to CBS deficiency were significantly improved by VB 12, which stimulated clearance of reactive oxygen species (ROS) by conserving GSH. Furthermore, EX-527 (a specific inhibitor of SIRT1) exposure counteracted the protective effect of VB 12 by promoting oxidative stress and aggravating mitochondrial damage without influencing CBS, indicating that vitamin B12 regulates SIRT1 to improve pancreatical damage by activating CBS. In conclusion, we found that VB 12 protected acute pancreatitis associated with oxidative stress via CBS/SIRT1 pathway.

Leveraging mRNA Sequences and Nanoparticles to Deliver SARS-CoV-2 Antigens In Vivo.

SARS-CoV-2 has become a pandemic worldwide; therefore, an effective vaccine is urgently needed. Recently, messenger RNAs (mRNAs) have emerged as a promising platform for vaccination. In this work, the untranslated regions (UTRs) of mRNAs are systematically engineered in order to enhance protein production. Through a comprehensive analysis of endogenous gene expression and de novo design of UTRs, the optimal combination of 5' and 3' UTR are identified and termed NASAR, which are 5- to 10-fold more efficient than the tested endogenous UTRs. More importantly, NASAR mRNAs delivered by lipid-derived TT3 nanoparticles trigger a dramatic expression of potential SARS-CoV-2 antigens. The antigen-specific antibodies induced by TT3-nanoparticles and NASAR mRNAs are over two orders of magnitude more than that induced by the FDA-approved lipid nanoparticle material MC3 in vaccinated mice. These NASAR mRNAs merit further development as alternative SARS-CoV-2 vaccines.