Significantly enhanced uranium extraction by intelligent light-driven nanorobot catchers with precise controllable moving trajectory.

Uranium, as the most essential resource for nuclear power production, provides 13% of global electricity demand, has attracted considerable attention. However, it is still a great challenge for uranium extraction from natural water like salt lakes as the background of high salinity and low concentration (3.3 ∼ 330 ppb). Meanwhile, current uranium extraction strategies are generally focus on extraction capacity or selectivity but neglect to enhance extraction rate. In this work, we designed a novel kind of NIR-driven intelligent nanorobots catchers (MSSA-AO) with amidoxime as claws for uranium capture, which showed almost 100% extraction rate and an ultrafast extraction rate. Importantly, high extraction capacity (221.5 mg g-1) and selectivity were taken into consideration as well as good regeneration performance. Furthermore, amidoxime NRCs boosted in extraction amount about 16.7% during the first 5 min with self-driving performance. Overall, this work suggests a new strategy for ultrafast extraction of uranium from natural water with low abundance selectively by self-propelled NRCs, showing great possibility in outdoor application and promising for meeting huge energy needs globally.

Redox-Regulated Synthetic Channels: Enabling Reversible Ion Transport by Modulating the Ion-Permeation Pathway.

Natural redox-regulated channel proteins often utilize disulfide bonds as redox sensors for adaptive regulation of channel conformations in response to diverse physiological environments. In this study, we developed novel synthetic ion channels capable of reversibly switching their ion-transport capabilities by incorporating multiple disulfide bonds into artificial systems. X-ray structural analysis and electrophysiological experiments demonstrated that these disulfide-bridged molecules possess well-defined tubular cavities and can be efficiently inserted into lipid bilayers to form artificial ion channels. More importantly, the disulfide bonds in these molecules serve as redox-tunable switches to regulate the formation and disruption of ion-permeation pathways, thereby achieving a transition in the transmembrane transport process between the ON and OFF states.

Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability in vitro and in vivo.

Ibrutinib is a first-line drug for the treatment of B-cell malignancies. BTKC481S mutation has led to drug resistance during clinical application. Herein, a novel BTK-targeting PROTAC molecule with better solubility and bioavailability was developed. Compound 15-271 has better solubility than ibrutinib and some reported BTK PROTACs. 15-271 has better liver microsomal stability than its analogues in multiple species. More importantly, 15-271 has a longer half-life and better bioavailability in vivo. The development strategy of compound 15-271 can be a general procedure for the optimization of other PROTACs.

Unimolecular Chiral Stepping Inversion Machine.

Intelligent molecular machines that are driven by light, electricity, and temperature have attracted considerable interest in the fields of chemistry, materials, and biology. Herein, a unimolecular chiral stepping inversion molecular machine (SIMM) was constructed by a coupling reaction between dibromo pillar[5]arene and a tetrathiafulvalene (TTF) derivative (PT3 and PT5). Compared with the longer aliphatic linker PT5, PT3 with a shorter aliphatic linker shows chiral stepping inversion, achieving chiral inversion under a two-electron redox potential. Benefiting from the successive reversible two-electron redox potential of TTF, the self-exclusion and self-inclusion conformational transformations of SIMM can proceed in two steps under redox, leading to the chirality step inversion in the pillar[5]arene core. Electrochemical experiments and circular dichroism (CD) spectra show that the redox processes can cause SIMM CD signaling to reversibly switch. More importantly, as the oxidant Fe(ClO4)3 was increased from 0.1 to 1 equiv, the CD spectral signal of SIMM disappeared at 1 equiv, and further addition of Fe(ClO4)3 resulted in the CD signal reversed from positive to negative at 309 nm, indicating that the chirality was reversed after chemical oxidation and reached a negative maximum with the addition of 2 equiv Fe(ClO4)3; thus, redox-triggered chiral stepping inversion was achieved. Furthermore, the chiral inversion can be restored to its original state after the addition of 2 equiv of reducing agent, sodium ascorbate. This work demonstrates unimolecular chiral stepping inversion, providing a new perspective on stimulus-responsive chirality in molecular machines.

Iterative Learning Control of Constrained Systems With Varying Trial Lengths Under Alignment Condition.

This brief is concerned with iterative learning control (ILC) of constrained multi-input multi-output (MIMO) nonlinear systems under the state alignment condition with varying trial lengths. A modified reference trajectory is constructed to meet the alignment condition by adjusting the reference trajectory to be spatially closed. Resorting to the barrier composite energy function (BCEF) approach, an adaptive ILC scheme is built to guarantee the bounded convergence of the resultant closed-loop system. Illustrative examples are presented to verify the validity of the proposed iteration scheme.

Bioinspired construction of magnetic nano stirring rods with radially aligned dual mesopores and intrinsic rapid adsorption of palladium.

Quick and precise recovery of palladium (Pd) from electronic waste remains a serious task, owing to the strong acid and complexity of chemical compounds in leachate. Here, bioinspired construction of magnetic nano stirring rod with radially aligned dual mesopores and abundant 8-aminoquinoline (MNSR-DM-AQ) is proposed for selective and rapid extraction of Pd(II) from highly acidic sample solutions. Benefit from the unique dual mesoporous (12.4 nm and 3.6 nm) and the stirring motion under an external magnetic field, MNSR-DM-AQ possesses enhanced adsorption capacity and kinetics, achieving 11.62 mg g-1 (97.2 % of the maximum adsorption capacity) in 15 min. Distribution coefficient (KD = 299.0 mL g-1), separation factor (α above 25.54) and concentration factor (CF = 230.2 mL g-1) reveal the excellent selectivity of MNSR-DM-AQ towards Pd(II) when comparing with the coexisting ions (Ca(II), Co(II), Cu(II), Fe(II), Mg(II), Ni(II), Pb(II), Zn(II)). The adsorption mechanisms of MNSR-DM-AQ are ion exchange and chelation due to a strong affinity between Pd(II) and N. Meanwhile, 96.82 % of the captured Pd(II) can be easily eluted within 15 min, and the adsorption capacity remains stable after five adsorption-desorption cycles. It is worthwhile to mention that MNSR-DM-AQ exhibits a high adsorption capacity of 8.39 mg g-1 from leachate of abandoned high-voltage patch capacitor, which is greatly desired in Pd(II) extraction from electronic waste.

Automated high-throughput genome editing platform with an AI learning in situ prediction model.

A great number of cell disease models with pathogenic SNVs are needed for the development of genome editing based therapeutics or broadly basic scientific research. However, the generation of traditional cell disease models is heavily dependent on large-scale manual operations, which is not only time-consuming, but also costly and error-prone. In this study, we devise an automated high-throughput platform, through which thousands of samples are automatically edited within a week, providing edited cells with high efficiency. Based on the large in situ genome editing data obtained by the automatic high-throughput platform, we develop a Chromatin Accessibility Enabled Learning Model (CAELM) to predict the performance of cytosine base editors (CBEs), both chromatin accessibility and the context-sequence are utilized to build the model, which accurately predicts the result of in situ base editing. This work is expected to accelerate the development of BE-based genetic therapies.

Synthesis of Polycarboxylate Viscosity Reducer and the Effect of Different Chain Lengths of Polyether on Viscosity Reduction of Heavy Oil.

Since there are not many studies on the application of polymeric surfactants in viscosity reduction emulsification of heavy oil, a series of polyether carboxylic acid-sulfonate polymeric surfactants were synthesized. The viscosity reduction performance and the effect of different chain lengths on the viscosity reduction effect were also investigated. The viscosity reduction, emulsification, wetting, and foaming performance tests showed that the viscosity reduction performance of this series of polymeric surfactants was excellent, with the viscosity reduction rate exceeding 95%, and the viscosity was reduced to 97 mPa·s by the polymeric surfactant with a molecular weight of 600 polyethers. It was also concluded that among the three surfactants with different side chains, the polymeric surfactant with a polyether molecular weight of 600, which is the medium side-chain length, had the best viscosity reduction performance. The study showed that the polyether carboxylic acid-sulfonate polymer surfactant had a promising application in the viscosity reduction of heavy oil.

A Highly Efficient Phosphorescence/Fluorescence Supramolecular Switch Based on a Bromoisoquinoline Cascaded Assembly in Aqueous Solution.

Despite ongoing research into photocontrolled supramolecular switches, reversible photoswitching between room-temperature phosphorescence (RTP) and delayed fluorescence is rare in the aqueous phase. Herein, an efficient RTP-fluorescence switch based on a cascaded supramolecular assembly is reported, which is constructed using a 6-bromoisoquinoline derivative (G3 ), cucurbit[7]uril (CB[7]), sulfonatocalix[4]arene (SC4A4), and a photochromic spiropyran (SP) derivative. Benefiting from the confinement effect of CB[7], initial complexation with CB[7] arouses an emerging RTP signal at 540 nm for G3 . This structure subsequently coassembles with amphiphilic SC4A4 to form tight spherical nanoparticles, thereby further facilitating RTP emission (≈12 times) in addition to a prolonged lifetime (i.e., 1.80 ms c.f., 50.1 µs). Interestingly, following cascaded assembly with a photocontrolled energy acceptor (i.e., SP), the efficient light-driven RTP energy transfer occurs when SP is transformed to its fluorescent merocyanine (MC) state. Ultimately, this endows the final system with an excellent RTP-fluorescence photoswitching property accompanied by multicolor tunable long-lived emission. Moreover, this switching process can be reversibly modulated over multiple cycles under alternating UV and visible photoirradiation. Finally, the prepared switch is successfully applied to photocontrolled multicolor cell labeling to offer a new approach for the design and fabrication of novel advanced light-responsive RTP materials in aqueous environments.

Characterization of the GATA Transcription Factor Family and Exploration of Their Relevance to Immune Infiltration and Tumor Microenvironment in Pancreatic Cancer.

BACKGROUND: Pancreatic cancer (PC) presents a phenomenal disease burden worldwide. The GATA transcription factor family is associated with a variety of human malignancies. However, the relation between GATA family members (GATAs) and PC has not been elucidated. METHODS: This study integrates large-scale bioinformatics database resources to analyze the expression patterns of GATAs in PC patients and explore their underlying function mechanism and relevance to immune infiltration and other different cell types in the tumor microenvironment in pancreatic cancer. First, the expression pattern of GATAs in pancreatic cancer was detected by the Oncomine database and the Gene Expression Profile Interaction Analysis (GEPIA2) database and verified through other datasets in the R2 platform. Then, we used the cBioPortal database and the Human Protein Atlas to assess the correlation between GATAs and clinicopathological features of PC. Then, survival analyses were performed to identify candidate prognostic factors in the GATA family in PC patients. Further, we performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network, immune-infiltration correlation analysis, and cell type analysis of the tumor microenvironment at the single-cell level to explain the function of GATAs in pancreatic cancer. RESULTS: We found that GATA3 and GATA6 were highly expressed in pancreatic cancer, and the expression levels of GATA4 and GATA6 correlated with the pathological stage, differentiation grade, and molecular subtype of pancreatic cancer. The survival analysis revealed that lower GATA4 of PC patients was associated with better outcomes, and higher GATA6 might be associated with longer OS. In addition, GATA3 was associated with immune cell infiltration of PC, and GATA6 was mainly distributed in the epithelial cells with ductal phenotype. CONCLUSION: This work tentatively identified GATA3, GATA4, and GATA6 in the GATA family associated with pancreatic cancer. GATA4 may serve as a prognostic factor for PC patients, and GATA6 may act as a subtype marker for PC. In addition, GATA3 may reflect the immune-infiltration status of PC.

Investigation of the antidepressant mechanism of combined Radix Bupleuri and Radix Paeoniae Alba treatment using proteomics analysis of liver tissue.

Depression is a chronic, common mental illness characterized by depressed mood, anxiety, insomnia, cognitive impairment, and even suicidal tendency. In traditional Chinese medicine theory, the cause of depression is deemed to be "stagnation of liver qi". So relieving "stagnation of liver qi" is effective for depression. The combination of Radix Bupleuri and Radix Paeoniae Alba, which is used to soothe the liver and relieve depression, has antidepressant effects, but the mechanisms of the effects are still unclear. In this study, a rat model of chronic unpredictable mild stress was established as a model of depression, and proteomics analysis was used to explore the potential mechanisms of this combination in alleviating depression. Biological information analysis was performed on the selected differential proteins, and the enriched pathways mainly included the Jak-STAT signaling pathway, valine, leucine, and isoleucine degradation, and oxidative phosphorylation. The expression of key proteins included metallothionein-1, cyclin-dependent kinase, ubiquitin carboxyl-terminal hydrolase-1, and Cryab was further verified by western blotting, and the results which were consistent with the proteomics results, confirmed the reliability of the proteomic analysis. The antidepressant mechanism of combined Radix Bupleuri and Radix Paeoniae Alba treatment may be related to the oxidative stress response, neuroplasticity, the immune response, and neuroprotection.

Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs.

Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic development, and reproduction. However, previous efforts for FAK blocking mainly focus on kinase inhibitors. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that allow direct post-translational knockdown of proteins via ubiquitination of a target protein by E3 ubiquitin ligase and subsequent proteasomal degradation. Here, we designed and synthesized a FAK PROTAC library with FAK inhibitor (PF562271 or VS6063) and CRBN E3 ligand. A novel FAK-targeting PROTAC, FC-11, showed a rapid and reversible FAK degradation with a picomolar of DC50 in various cell lines in vitro, which imply that FAK-PROTACs could be useful as expand tools for studying functions of FAK in biological system and as potential therapeutic agents.

Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects.

The BCR-ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR-ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR-ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR-ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-type and T315I-mutated BCR-ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.

Assessment of prophylactic antibiotics administration for acute pancreatitis: a meta-analysis of randomized controlled trials.

BACKGROUND: Recent evidence has shown that prophylactic antibiotic treatment in patients with acute pancreatitis is not associated with a significant decrease in mortality or morbidity. The use and efficacy of prophylactic antibiotic treatment in acute pancreatitis remain controversial. This meta-analysis was conducted to assess whether antibiotic prophylaxis is beneficial in patients with acute pancreatitis. METHODS: We searched randomized controlled trials (RCTs) of prophylactic use of antibiotics using Medline (PubMed), Embase, the Cochrane Library, and Web of Science. The data were analyzed using Review Manager 5.3 software. We performed pooled analyses for infected pancreatic necrosis, mortality, surgical intervention, and non-pancreatic infection. Odds ratios (ORs) from each trial were pooled using a random or fixed effects model, depending on the heterogeneity of the included studies. Sub-group analysis or sensitivity analysis was conducted to explore potential sources of heterogeneity, when necessary. RESULTS: Totally, 11 RCTs involving 747 participants were included, with an intervention group (prophylactic use of antibiotics, n = 376) and control group (n = 371). No significant differences were found regarding antibiotic prophylaxis with respect to incidence of infected pancreatic necrosis (OR, 0.74; 95% confidence interval [CI], 0.50-1.09; P = 0.13), surgical intervention (OR, 0.92; 95% CI, 0.62-1.38; P = 0.70), and morality (OR, 0.71; 95% CI, 0.44-1.15; P = 0.16). However, antibiotic prophylaxis was associated with a statistically significant reduction in the incidence of non-pancreatic infection (OR, 0.59; 95% CI, 0.42-0.84; P = 0.004). CONCLUSIONS: Prophylactic antibiotics can reduce the incidence of non-pancreatic infection in patients with AP.

A chemical approach for global protein knockdown from mice to non-human primates.

Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (BTK). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in animals, particularly in large animals, for which gene-targeted knockout strategies may remain unfeasible.