Multifunctional Additive Enables a "5H" PEO Solid Electrolyte for High-Performance Lithium Metal Batteries.

The solid-state battery with a lithium metal anode is a promising candidate for next-generation batteries with improved energy density and safety. However, the current polymer electrolytes still cannot fulfill the demands of solid-state batteries. In this work, we propose a "5H" poly(ethylene oxide) (PEO) electrolyte via introducing a multifunctional additive of tris(pentafluorophenyl)borane (TPFPB) for high-performance lithium metal batteries. The addition of TPFPB improves the ionic conductivity from 6.08 × 10-5 to 1.54 × 10-4 S cm-1 via reducing the crystallinity of the PEO electrolyte and enhances the lithium-ion transference number from 0.19 to 0.53 via anion trapping due to its Lewis acid nature. Furthermore, the fluorine and boron segments from TPFPB can optimize the composition of the solid-electrolyte interphase and cathode-electrolyte interphase, providing a high electrochemical stability window over 4.6 V of the PEO electrolyte along with significantly improved interface stability. At last, TPFPB can ensure improved safety through a self-extinguishing effect. As a result, the "5H" electrolyte enables the Li/Li symmetric cells to achieve a stable cycle over 2200 h at the current density of 0.2 mA cm-2 with a capacity of 0.2 mA h cm-2; the LiFePO4/Li full cells with a high LFP loading of 8 mg cm-2 exhibits decay-free capacity of 140 mA h g-1 (99% capacity retention) after 100 cycles; and the NCM811/Li cells exhibit a high capacity of 160 mA h g-1 after 50 cycles at 0.5 C. This work presents an innovative approach to utilizing a "5H" electrolyte for high-performance solid-state lithium batteries.

Causal association between dried fruit intake and risk of osteoarthritis: A Mendelian randomization study.

This study aimed to examine whether dried fruit intake is causally associated with Osteoarthritis (OA). A two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median (WM), and MR-Egger regression methods was performed. We used the publicly available summary statistics data sets of genome-wide association studies (GWAS) meta-analyses for dried fruit intake in individuals included in the UK Biobank (n = 421,764; MRC-IEU consortium) as the exposure and a GWAS publicly available in PubMed for OA (total n = 484,598; case = 39,515, control = 445,083) as the outcome. We selected 41 single nucleotide polymorphisms at genome-wide significance from GWASs on dried fruit intake as the instrumental variables. The IVW method showed evidence to support a causal association between dried fruit intake and OA (beta = -0.020, SE = 0.009, P = .039). MR-Egger regression indicated no directional pleiotropy (intercept = 1E-05; P = .984), but it showed no causal association between dried fruit intake and OA (beta = -0.020, SE = 0.043, P = .610). However, the WM approach yielded evidence of a causal association between dried fruit intake and OA (beta = -0.026, SE = 0.012, P = .026). Cochran's Q test showed the existence of heterogeneity, but the statistics of I2 showed low heterogeneity. The results of MR analysis support that dried fruit intake may be causally associated with a decreased risk of OA.

Effect of the combined binding of topotecan and catechin/protocatechuic acid to a pH-sensitive DNA tetrahedron on release and cytotoxicity: Spectroscopic and calorimetric studies.

The therapeutic efficacy of chemotherapy drugs can be effectively improved through the dual effects of their combination with natural polyphenols and the delivery of targeted DNA nanostructures. In this work, the interactions of topotecan (TPT), (+)-catechin (CAT), or protocatechuic acid (PCA) with a pH-sensitive DNA tetrahedron (MUC1-TD) in the binary and ternary systems at pHs 5.0 and 7.4 were investigated by fluorescence spectroscopy and calorimetry. The intercalative binding mode of TPT/CAT/PC to MUC1-TD was confirmed, and their affinity was ranked in the order of PCA > CAT > TPT. The effects of the pH-sensitivity of MUC1-TD and different molecular structures of CAT and PCA on the loading, release, and cytotoxicity of TPT were discussed. The weakened interaction under acidic conditions and the co-loading of CAT/PCA, especially PCA, improved the release of TPT loaded by MUC1-TD. The targeting of MUC1-TD and the synergistic effect with CAT/PCA, especially CAT, enhanced the cytotoxicity of TPT on A549 cells. For L02 cells, the protective effect of CAT/PCA reduced the damage caused by TPT. The single or combined TPT loaded by MUC1-TD was mainly concentrated in the nucleus of A549 cells. This work will provide key information for the combined application of TPT and CAT/PCA loaded by DNA nanostructures to improve chemotherapy efficacy and reduce side effects.

Multi-spectroscopic and molecular docking studies for the pH-dependent interaction of ß-lactoglobulin with (-)-epicatechin gallate and/or piceatannol: Influence on antioxidant activity and stability.

(-)-Epicatechin gallate (ECG) and piceatannol (PIC) are commonly polyphenols with excellent biological activities. ß-Lactoglobulin (BLG) is a food-grade globule protein and its morphologies are sensitive to pH. This study used experimental and computational methods to determine the interaction of single or combined ECG and PIC with BLG at different pHs. The static quenching process was determined through fluorescence and ultraviolet-visible spectroscopy. Compared with ECG, PIC could significantly bind to BLG with higher affinity. Their binding affinity for BLG with different morphologies followed the tendency of monomer > dimer > tetramer. The negative contribution of van der Waals forces, electrostatic interactions, and hydrogen bonds to ΔHo exceeded the positive contribution of hydrophobic interactions in the spontaneous and exothermic process. The reduced binding affinity in the ternary systems demonstrated the competitive binding between ECG and PIC on BLG, and the hinder effect of ECG or PIC was enhanced with increasing pH. Molecular docking studies revealed the same binding sites of ECG and PIC on various conformations of BLG and identical driven forces as thermodynamic results. Tryptophan and tyrosine were the main participators in the BLG + ECG and BLG + PIC systems, respectively. The conformational changes in the binary and ternary systems could be ascertained through synchronous fluorescence, circular dichroism, and dynamic light scattering. Furthermore, the effects of pH and BLG encapsulation on the antioxidant capacity and stability of ECG or PIC were also implemented. ECG or PIC was the most stable in the (BLG + PIC) + ECG system at pH 6.0. This study could clarify the interaction mechanism between ECG/PIC and BLG and elucidate the pH effect on their binding information. The results will provide basic support for their usage in food processing and applications.

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis.

BACKGROUND: Malaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive. METHODS: We first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays. RESULTS: The results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects. CONCLUSIONS: In conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel. Video Abstract.

Sulfur Vacancies and 1T Phase-Rich MoS2 Nanosheets as an Artificial Solid Electrolyte Interphase for 400 Wh kg-1 Lithium Metal Batteries.

Constructing large-area artificial solid electrolyte interphase (SEI) to suppress Li dendrites growth and electrolyte consumption is essential for high-energy-density Li metal batteries (LMBs). Herein, chemically exfoliated ultrathin MoS2 nanosheets (EMoS2 ) as an artificial SEI are scalable transfer-printed on Li-anode (EMoS2 @Li). The EMoS2 with a large amount of sulfur vacancies and 1T phase-rich acts as a lithiophilic interfacial ion-transport skin to reduce the Li nucleation overpotential and regulate Li+ flux. With favorable Young's modulus and homogeneous continuous layered structure, the proposed EMoS2 @Li effectively suppresses the growth of Li dendrites and repeat breaking/reforming of the SEI. As a result, the assembled EMoS2 @Li||LiFePO4 and EMoS2 @Li||LiNi0.8 Co0.1 Mn0.1 O2 batteries demonstrate high-capacity retention of 93.5% and 92% after 1000 cycles and 300 cycles, respectively, at ultrahigh cathode loading of 20 mg cm-2 . Ultrasonic transmission technology confirms the admirable ability of EMoS2 @Li to inhibit Li dendrites in practical pouch batteries. Remarkably, the Ah-class EMoS2 @Li||LiNi0.8 Co0.1 Mn0.1 O2 pouch battery exhibits an energy density of 403 Wh kg-1 over 100 cycles with the low negative/positive capacity ratio of 1.8 and electrolyte/capacity ratio of 2.1 g Ah-1 . The strategy of constructing an artificial SEI by sulfur vacancies-rich and 1T phase-rich ultrathin MoS2 nanosheets provides new guidance to realize high-energy-density LMBs with long cycling stability.

High-Yield Synthesis of Lacto-N-Neotetraose from Glycerol and Glucose in Engineered Escherichia coli.

Lacto-N-neotetraose (LNnT) is a neutral human milk oligosaccharide with important biological functions. However, the low LNnT productivity and the incomplete conversion of the intermediate lacto-N-tetraose II (LNT II) currently limited the sustainable biosynthesis of LNnT. First, the LNnT biosynthetic module was integrated in Escherichia coli. Next, the LNnT export system was optimized to alleviate the inhibition of intracellular LNnT synthesis. Furthermore, by utilizing rate-limiting enzyme diagnosis, the expressions of LNnT synthesis pathway genes were finely regulated to further enhance the production yield of LNnT. Subsequently, a strategy of cofermentation using a glucose/glycerol (4:6, g/g) mixed feed was employed to regulate carbon flux distribution. Finally, by overexpressing key transferases, LNnT and LNT II titers reached 112.47 and 7.42 g/L, respectively, in a 5 L fermenter, and 107.4 and 2.08 g/L, respectively, in a 1000 L fermenter. These are the highest reported titers of LNnT to date, indicating its significant potential for industrial production.

Pentafluoro(phenoxy)cyclotriphosphazene Stabilizes Electrode/Electrolyte Interfaces for Sodium-Ion Pouch Cells of 145 Wh Kg-1.

Sodium-ion batteries are competitive candidates for large-scale energy storage batteries due to the abundant sodium resource. However, the electrode interface in the conventional electrolyte is unstable, deteriorating the cycle life of the cells. Introducing functional electrolyte additives can generate stable electrode interfaces. Here, pentafluoro(phenoxy)cyclotriphosphazene (FPPN) serves as a functional electrolyte additive to stabilize the interfaces of the layered oxide cathode and the hard carbon anode. The fluorine substituting groups and the π-π conjugated ─PN─ structure decrease the lowest unoccupied molecular orbital and increase the highest occupied molecular orbital of FPPN, respectively, realizing the preferential reduction and oxidization of FPPN on the anode and cathode simultaneously, which results in the formation of a uniform, ultrathin, and inorganic-rich solid electrolyte interlayer and cathode electrolyte interphase. The sodium-ion pouch cells of 5 Ah capacity rather than coin cells are assembled to evaluate the effect of FPPN. It can retain a high capacity of 4.46 Ah after 1000 cycles, corresponding to a low decay ratio of 0.01% per cycle. The pouch cell also achieves a high energy density of 145 Wh kg-1 and a wide operating temperature of -20-60 °C. This work can attract more attention to the rational electrolyte design for practical applications.

Abnormal functional connectivity of the reward network is associated with social communication impairments in autism spectrum disorder: A large-scale multi-site resting-state fMRI study.

BACKGROUND: The social motivation hypothesis proposes that the social deficits of autism spectrum disorder (ASD) are related to reward system dysfunction. However, functional connectivity (FC) patterns of the reward network in ASD have not been systematically explored yet. METHODS: The reward network was defined as eight regions of interest (ROIs) per hemisphere, including the nucleus accumbens (NAc), caudate, putamen, anterior cingulate cortex (ACC), ventromedial prefrontal cortex (vmPFC), orbitofrontal cortex (OFC), amygdala, and insula. We computed both the ROI-wise resting-state FC and seed-based whole-brain FC in 298 ASD participants and 348 typically developing (TD) controls from the Autism Brain Imaging Data Exchange I dataset. Two-sample t-tests were applied to obtain the aberrant FCs. Then, the association between aberrant FCs and clinical symptoms was assessed with Pearson's correlation or Spearman's correlation. In addition, Neurosynth Image Decoder was used to generate word clouds verifying the cognitive functions of the aberrant pathways. Furthermore, a three-way multivariate analysis of variance (MANOVA) was conducted to examine the effects of gender, subtype and age on the atypical FCs. RESULTS: For the within network analysis, the left ACC showed weaker FCs with both the right amygdala and left NAc in ASD compared with TD, which were negatively correlated with the Autism Diagnostic Observation Schedule (ADOS) total scores and Social Responsiveness Scale (SRS) total scores respectively. For the whole-brain analysis, weaker FC (i.e., FC between the left vmPFC and left calcarine gyrus, and between the right vmPFC and left precuneus) accompanied by stronger FC (i.e., FC between the left caudate and right insula) were exhibited in ASD relative to TD, which were positively associated with the SRS motivation scores. Additionally, we detected the main effect of age on FC between the left vmPFC and left calcarine gyrus, of subtype on FC between the right vmPFC and left precuneus, of age and age-by-gender interaction on FC between the left caudate and right insula. CONCLUSIONS: Our findings highlight the crucial role of abnormal FC patterns of the reward network in the core social deficits of ASD, which have the potential to reveal new biomarkers for ASD.

Impaired segregation of the attention deficit hyperactivity disorder related pattern in children.

BACKGROUND: Inattention is a key characteristic of attention deficit hyperactivity disorder (ADHD). Specific brain abnormalities associated with this symptom form a discernible pattern related with ADHD in children (i.e., ADHD related pattern) in our earlier research. The developmental processes of segregation and integration may be crucial to ADHD. However, how brains reconfigure these processes of the ADHD related pattern in different subtypes of ADHD and across sexes remain unclear. METHODS: Nested-spectral partition method was applied to identify effects of subtype and sex on segregation and integration of the ADHD related pattern, using 145 ADHD patients and 135 typically developing controls (TDC) aged 7-14. Relationships between the measures and inattention symptoms were also investigated. RESULTS: Children with ADHD exhibited lower segregation of the ADHD related pattern (p = 1.17 × 10-8) than TDCs. Only the main effect of subtype was significant (p = 1.14 × 10-5). Both ADHD-C (p = 2.16 × 10-6) and ADHD-I (p = 2.87 × 10-6) patients had lower segregation components relative to the TDC. Moreover, segregation components were negatively correlated with inattention scores. CONCLUSIONS: This study identified impaired segregation in the ADHD related pattern of children with ADHD and found shared neural bases among different subtypes and sexes.

Moxibustion ameliorates osteoarthritis by regulating gut microbiota via impacting cAMP-related signaling pathway.

BACKGROUND: Osteoarthritis (OA) is a prevalent progressive disorder. Moxibustion has found widespread use in clinical practice for OA, while its underlying mechanism remains elusive. OBJECTIVE: To investigate whether moxibustion can ameliorate OA by influencing the metabolic processes in OA and to elucidate the specific metabolic mechanisms involved. METHODS: C57BL/6J WT mice were randomly assigned to one of three groups: the SHAM group, the ACLT group, and the ACLT+M group. In the ACLT+M group, mice underwent moxibustion treatment at acupoints Shenshu (BL23) and Zusanli (ST36) for a continuous period of 28 days, with each session lasting 20 min. We conducted a comprehensive analysis to assess the impact of moxibustion on OA, focusing on pathological changes, intestinal flora composition, and serum metabolites. RESULTS: Moxibustion treatment effectively mitigated OA-related pathological changes. Specifically, moxibustion treatment resulted in the amelioration of articular cartilage damage, synovial inflammation, subchondral bone sclerosis when compared to the ACLT group. Moreover, 16S rDNA sequencing analysis revealed that moxibustion treatment positively influenced the composition of the flora, making it more similar to that of the SHAM group. Notably, moxibustion treatment led to a reduction in the abundance of Ruminococcus and Proteobacteria in the intestine. In addition, non-targeted metabolomics analysis identified 254 significantly different metabolites between the groups. Based on KEGG pathway analysis and the observed impact of moxibustion on OA-related inflammation, moxibustion therapy is closely associated with the cAMP-related signaling pathway. CONCLUSION: Moxibustion can relieve OA by regulating intestinal flora and via impacting cAMP-related signaling pathway.

Neighbored-attention U-net (NAU-net) for diabetic retinopathy image segmentation.

Background: Diabetic retinopathy-related (DR-related) diseases are posing an increasing threat to eye health as the number of patients with diabetes mellitus that are young increases significantly. The automatic diagnosis of DR-related diseases has benefited from the rapid development of image semantic segmentation and other deep learning technology. Methods: Inspired by the architecture of U-Net family, a neighbored attention U-Net (NAU-Net) is designed to balance the identification performance and computational cost for DR fundus image segmentation. In the new network, only the neighboring high- and low-dimensional feature maps of the encoder and decoder are fused by using four attention gates. With the help of this improvement, the common target features in the high-dimensional feature maps of encoder are enhanced, and they are also fused with the low-dimensional feature map of decoder. Moreover, this network fuses only neighboring layers and does not include the inner layers commonly used in U-Net++. Consequently, the proposed network incurs a better identification performance with a lower computational cost. Results: The experimental results of three open datasets of DR fundus images, including DRIVE, HRF, and CHASEDB, indicate that the NAU-Net outperforms FCN, SegNet, attention U-Net, and U-Net++ in terms of Dice score, IoU, accuracy, and precision, while its computation cost is between attention U-Net and U-Net++. Conclusion: The proposed NAU-Net exhibits better performance at a relatively low computational cost and provides an efficient novel approach for DR fundus image segmentation and a new automatic tool for DR-related eye disease diagnosis.

Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the Tripterygium wilfordii plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC.

Functional characterization of a cold related flavanone 3-hydroxylase from Tetrastigma hemsleyanum: an in vitro, in silico and in vivo study.

Tetrastigma hemsleyanum Diels et Gilg, a traditional Chinese medicine, frequently suffers from cold damage in the winter, leading to lower yields. There is a pressing need to improve cold resistance; however, the mechanisms underlying T. hemsleyanum responses to cold stress are still not clearly understood. Here, we explored the function of the flavanone 3-hydroxylase gene (ThF3H) in T. hemsleyanum under cold treatment. The open reading frame of ThF3H is 1092 bp and encodes 363 amino acid residues. In vitro, the ThF3H enzyme was expressed in E. coli and successfully catalyzed naringenin and eriodictyol into dihydrokaempferol and dihydroquercetin, respectively. ThF3H exhibited a higher affinity for naringenin than for eriodictyol, which was in accordance with an in silico molecular docking analysis. The optimal pH and temperature for ThF3H activity were 7.0 and 30 °C, respectively. In vivo, overexpression of the ThF3H gene enhanced the cold tolerance of transgenic Arabidopsis lines, which was likely due to the increase in flavonoids. Collectively, the function of a cold-related ThF3H in the flavonoid biosynthesis pathway may be helpful for improving the cold tolerance of T. hemsleyanum through molecular breeding techniques.

Celastrol induces premature ovarian insufficiency by inducing apoptosis in granulosa cells.

Celastrol, a natural compound purified from the Chinese herb Tripterygium wilfordii Hook. f., has excellent pharmacological activity for the treatment of various diseases. Assessing the safety of its use is essential for its development into a clinical medicine. However, research assessing its toxicity on the female reproductive system has never been reported. In this study, the ovarian toxicity of celastrol and its underlying mechanism were investigated. We found that celastrol induced premature ovarian insufficiency and apoptosis in granulosa cells. Activity-based protein profiling results showed that high mobility group box 1 was a candidate target protein of celastrol. Celastrol directly bound to Cys106 of high mobility group box 1. Knocking down high mobility group box 1 induced apoptosis of granulosa cells, while overexpression of this gene reversed celastrol-induced apoptosis. Celastrol treatment upregulated p21 transcription, but overexpression of high mobility group box 1 reversed this upregulation. Thus, Celastrol induces premature ovarian insufficiency and apoptosis in granulosa cells by directly binding to high mobility group box 1 and interfering with its biological function to regulate p21 transcription. This study provides valuable information for assessing the safety of the clinical application of celastrol on female patients.

Abnormal individualized peak functional connectivity toward potential repetitive transcranial magnetic stimulation treatment of autism spectrum disorder.

Functional connectivity (FC) derived from resting-state functional magnetic resonance imaging has been widely applied to guide precise repetitive transcranial magnetic stimulation (rTMS). The left, right, and bilateral dorsolateral prefrontal cortices (DLPFC) have been used as rTMS treatment target regions for autism spectrum disorder (ASD), albeit with moderate efficacy. Thus, we aimed to develop an individualized localization method for rTMS treatment of ASD. We included 266 male ASDs and 297 male typically-developed controls (TDCs) from the Autism Brain Imaging Data Exchange Dataset. The nucleus accumbens (NAc) was regarded as a promising effective region, which was used as a seed and individualized peak FC strength in the DLPFC was compared between ASD and TDC. Correlation analysis was conducted between individualized peak FC strength and symptoms in ASD. We also investigated the spatial distribution of individualized peak FC locations in the DLPFC and conducted voxel-wise analysis to compare NAc-based FC between the two groups. ASD showed stronger peak FC in the right DLPFC related to TDC (Cohen's d = -.19, 95% CI: -0.36 to -0.03, t = -2.30, p = .02). Moreover, negative correlation was found between the peak FC strength in the right DLPFC and Autism Diagnostic Observation Schedule (ADOS) scores, which assessed both the social communication and interaction (r = -.147, p = .04, uncorrected significant), and stereotyped behaviors and restricted interests (r = -.198, p = .02, corrected significant). Peak FC locations varied substantially across participants. No significant differences in NAc-based FC in the DLPFC were found in the voxel-wise comparison. Our study supports the use of individualized peak FC-guided precise rTMS treatment of male ASD. Moreover, stimulating the right DLPFC might alleviate core symptoms of ASD.

Thermodynamic and cellular studies of doxorubicin/daunorubicin loaded by a DNA tetrahedron for diagnostic imaging, chemotherapy, and gene therapy.

The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In this study, we designed an antisense oligonucleotides (ASOs)-linked DNA tetrahedron (ASOs-TD). The detection limit of ASOs-TD for MDR1 mRNA was 0.05 µM. By using fluorescence spectroscopy and isothermal titration calorimetry (ITC), the interactions between doxorubicin (DOX) /daunorubicin (DAU) and ASOs-TD were investigated. The number of binding sites (n), binding constant (Ka), entropy change (ΔSo), enthalpy change (ΔHo) and Gibbs free energy change (ΔGo) were obtained. The intercalation of DOX/DAU with ASOs-TD was demonstrated by differential scanning calorimetry (DSC) and quenching researches of potassium ferricyanide K4[Fe(CN)6]. The in vitro release rate of DOX/DAU loaded in ASOs-TD was accelerated by deoxyribonuclease I (DNase I). In vitro cytotoxicity proved the good gene therapy effect of ASOs-TD and the increased cytotoxicity of DOX/DAU to MCF-7/ADR cells. The results of confocal laser scanning microscope (CLSM) suggested that ASOs-TD could effectively identify drug-resistant cells due to its good imaging ability for MDR1 mRNA. This work offers theoretical significance for overcoming MDR using DNA nanostructures which combine diagnostic imaging, chemotherapy, and gene therapy.

Metabolic Engineering of Escherichia coli for High-Level Production of Lacto-N-neotetraose and Lacto-N-tetraose.

Lacto-N-neotetraose (LNnT) and lacto-N-tetraose (LNT) are important oligosaccharides found in breast milk and are commonly used as nutritional supplements in infant formula. We used metabolic engineering techniques to optimize the modified Escherichia coli BL21 star (DE3) strain for efficient synthesis of LNnT and LNT using ß-1,4-galactosyltransferase (HpgalT) from Helicobacter pylori and ß-1,3-galactosyltransferase (SewbdO) from Salmonella enterica subsp. salamae serovar, respectively. Further, we optimized the expression of three key genes, lgtA, galE, and HpgalT (SewbdO), to synthesize LNnT or LNT and deleted several genes (ugd, ushA, agp, wcaJ, otsA, and wcaC) to block competition in the UDP-galactose synthesis pathway. The optimized strain produced LNnT or LNT with a titer of 22.07 or 48.41 g/L, respectively, in a supplemented batch culture, producing 0.41 or 0.73 g/L/h, respectively. The strategies used in this study contribute to the development of cell factories for high-level LNnT and LNT and their derivatives.

A Localized High-Concentration Water/Organic Hybrid Electrolyte for 2.5 V Li4Ti5O12/LiMn2O4 Batteries.

The "solvent-in-salt" electrolytes for an aqueous system, including "water-in-salt" electrolytes and "bisolvent-in-salt" electrolytes, have shown significantly improved electrochemical stability toward low-voltage anodes and high-voltage cathodes. However, the heavy use of salt raises concerns of high cost, high viscosity, inferior wettability, and poor low-temperature performance. Herein, a "localized bisolvent-in-salt electrolyte" is proposed by introducing 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether (TTE) as the diluent to the high-concentration water/sulfolane hybrid (BSiS-SL) electrolytes, forming a ternary solvent-based electrolyte, Li(H2O)0.9SL1.3·TTE1.3 (HS-TTE). The introduction of TTE dilutes the compact ionic clusters, while the original primary Li+ solvation structure remains, and in the meantime, boosts the formation of a robust solid electrolyte interphase. As a result, a wide electrochemically stable window of 4.4 V is achieved. In comparison with the bisolvent BSiS-SL system, the trisolvent HS-TTE electrolyte exhibits a low salt concentration of 2.1 mol kg-1, resulting in drastically reduced viscosity, superb separator wettability, and largely improved low-temperature performance. The constructed 2.5 V Li4Ti5O12/LiMn2O4 cell shows an excellent capacity retention of 80.7% after 800 cycles, and the cell can even work at -30 °C. With these extraordinary advantages, the fundamental designing strategy of the HS-TTE electrolyte developed in this work can promote the practical applications of solvent-in-salt electrolytes.

Mortality burden based on the associations of ambient PM2.5 with cause-specific mortality in China: Evidence from a death-spectrum wide association study (DWAS).

Although studies have estimated the associations of PM2.5 with total mortality or cardiopulmonary mortality, few have comprehensively examined cause-specific mortality risk and burden caused by ambient PM2.5. Thus, this study investigated the association of short-term exposure to PM2.5 with cause-specific mortality using a death-spectrum wide association study (DWAS). Individual information of 5,450,764 deaths during 2013-2018 were collected from six provinces in China. Daily PM2.5 concentration in the case and control days were estimated by a random forest model. A time-stratified case-crossover study design was applied to estimate the associations (access risk, ER) of PM2.5 with cause-specific mortality, which was then used to calculate the population-attributable fraction (PAF) of mortality and the corresponding mortality burden caused by PM2.5. Each 10 µg/m3 increase in PM2.5 concentration (lag03) was associated with a 0.80 % [95 % confidence interval (CI): 0.73 %, 0.86 %] rise in total mortality. We found greater mortality effect at PM2.5 concentrations < 50 µg/m3. Stratified analyses showed greater ERs in females (1.01 %, 95 %CI: 0.91 %, 1.11 %), children ≤ 5 years (2.17 %, 95 %CI: 0.85 %, 3.51 %), and old people ≥ 70 years. We identified 33 specific causes (level 2) of death which had significant associations with PM2.5, including 16 circulatory diseases, 9 respiratory diseases, and 8 other causes. The PAF estimated based on the overall association between PM2.5 and total mortality was 3.16 % (95 %CI: 2.89 %, 3.40 %). However, the PAF was reduced to 2.88 % (95 %CI: 1.88 %, 3.81 %) using the associations of PM2.5 with 33 level 2 causes of death, based on which 250.15 (95 %CI: 163.29, 330.93) thousand deaths were attributable to short-term PM2.5 exposure across China in 2019. Overall, this study provided a comprehensive picture on the death-spectrum wide association between PM2.5 and morality in China. We observed robust positive cause-specific associations of PM2.5 with mortality risk, which may provide more precise basis in assessing the mortality burden of air pollution.