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Background Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects. Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs (miRNAs) after exercise and found that some of them act as exerkines. However, whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown. Methods A 9-day treadmill training was used as an exercise model in C57BL/6 mice. Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p (miR-122-5p). Human umbilical vein endothelial cells were used in vitro. Results Among these differentially expressed extracellular vesicle miRNAs, miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro. Exercise increased circulating levels of miR-122-5p, which was produced mainly by the liver and shuttled by extracellular vesicles in mice. Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles, and exercise-improved muscle performance in mice. Mechanistically, miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells, and miR-122-5p upregulated endothelial cell fatty-acid use by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT1). In addition, miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice. Conclusion These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p, which enhances fatty acid use by targeting AGPAT1 in endothelial cells, highlighting the therapeutic potential of miR-122-5p in tissue repair.

Three-dimensional (3D) network structure of metal–organic framework (MOF) can accommodate outstanding electrocatalysis performances, but always collapse during the conversion to active materials or applications process. How to maintain the 3D network when producing active species is of great importance for full application of MOF. Herein, a new MOF material, In[Co(CN)6] (In-Co PBA) nanocubes, are firstly synthesized. Through a controlled low-temperature deligandation process, the In-Co PBA nanocubes are transformed to a novel In2O3@In-Co PBA quasi-MOF nanocubes, which basically retain the 3D porous structure of PBA but with in situ generated In2O3 nanoparticles inside. When used as CO2RR electrocatalyst, such a novel cubic composite structure exhibits excellent performances with faradaic efficiency of 85% for formate at a potential of −0.96 V and with current density of 31.5 mA·cm−2 at −1.32 V, surpassing most of the reported indium-based catalysts. The excellent performance can be attributed to the special composite structure, which provides not only active sites by In2O3 nanoparticles to catalyze CO2RR, but also the 3D porous framework by quasi-MOF to accelerate gaseous exchange and electrolyte permeation and prevent the electrode choking. This work offers a new strategy for the design of post-transition metal catalysts and the structure design of quasi-MOF.

Flexible fluorinated multi-walled carbon nanotube/polyarylene ether nitrile porous metacomposite film (FMWCNT/PEN) with negative permittivity has been fabricated via a delayed phase inversion method with a low content of FMWCNT.

BACKGROUND Cooking oil is an indispensable component of the human diet. However, oils usually undergo thermal oxidation. Oxidized soybean oil (OSO) has been shown to have detrimental effects on humans and has emerged as a root cause of many chronic diseases. The objective of this work was to evaluate the effects of puerpera exposure to OSO on kidney damage in the mother and offspring using lactating rats as an experimental model. RESULTS Pathological sections and ultrastructure showed that OSO exposure resulted in various levels of damage to lactating rats and their offspring. OSO induced oxidative stress in the kidneys of lactating rats, as evidenced by increased levels of hydrogen peroxide, interleukin (IL)-1β, and IL-8. OSO increased the activities of glutathione peroxidase and superoxide dismutase. OSO upregulated the expression of apoptosis-related genes, nuclear factor-erythroid 2-related factor 2 (Nrf2), and nuclear factor κB-related inflammatory factor genes. In the offspring of the OSO-exposed mothers, hydrogen peroxide, malondialdehyde, IL-6, and tumor necrosis factor-alpha contents were increased. Furthermore, OSO enhanced the levels of Nrf2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, and p65 and decreased B-cell lymphoma 2. CONCLUSION These findings indicated that the kidneys of two generations of rats were compromised by oxidative damage when fed OSO during lactation. This study provides evidence for increasing the genes expression of the Nrf2/heme oxygenase 1 pathway to alleviate the kidney damage caused by OSO in the mother and offspring. © 2021 Society of Chemical Industry.

Selective detection of multiple analytes in a compact design with dual-modality and theranostic features presents great challenges. Herein, we wish to report a coumarin-thiazolidine masked D -penicillamine based dual-modality fluorescent probe COU-DPA-1 for selective detection, differentiation, and detoxification of multiple heavy metal ions (Ag+, Hg2+, Cu2+). The probe shows divergent fluorescence (FL) /circular dichroism (CD) responses via divergent bond-cleavage cascade reactions (metal ion promoted C-S cleavage and hydrolysis at two distinctive cleavage sites): FL “turn-off” and CD “turn-on” for Ag+ (no hydrolysis), FL “turn-on” and CD “turn-off” for Hg2+ (imine hydrolysis), and FL “self-threshold ratiometric” and CD “turn-off” for excess Cu2+ (lactone and imine hydrolysis), providing the first example of a fluorescence/CD dual-modality probe for multiple species with complimentary responses. Moreover, the bond-cleavage cascade reactions also lead to the formation of D -penicillamine heavy metal ion complexes for potential detoxification treatments.

Vascular mitochondria constantly integrate signals from environment and respond accordingly to match vascular function to metabolic requirements of the organ tissues, while mitochondrial dysfunction contributes to vascular aging and pathologies such as atherosclerosis, stenosis, and hypertension. As an effective lifestyle intervention, exercise induces extensive mitochondrial adaptations through vascular mechanical stress and the increased production and release of reactive oxygen species and nitric oxide that activate multiple intracellular signaling pathways, among which peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays a critical role. PGC-1α coordinates mitochondrial quality control mechanisms to maintain a healthy mitochondrial pool and promote endothelial nitric oxide synthase activity in vasculature. The mitochondrial adaptations to exercise improve bioenergetics, balance redox status, protect endothelial cells against detrimental insults, increase vascular plasticity, and ameliorate aging-related vascular dysfunction, thus benefiting vascular health. This review highlights recent findings of mitochondria as a central hub integrating exercise-afforded vascular benefits and its underlying mechanisms. A better understanding of the mitochondrial adaptations to exercise will not only shed light on the mechanisms of exercise-induced cardiovascular protection, but may also provide new clues to mitochondria-oriented precise exercise prescriptions for cardiovascular health.

Rapid and sensitive point-of-care testing (POCT) is an extremely critical mission in practical applications, especially for rigorous military medicine, home health care, and in the third world. Here, we report a visual POCT method for adenosine triphosphate (ATP) detection based on Taylor rising in the corner of quadratic geometries between two rod surfaces. We discuss the principle of Taylor rising, demonstrating that it is significantly influenced by contact angle, surface tension, and density of the sample, which are controlled by ATP-dependent rolling circle amplification (RCA). In the presence of ATP, RCA reaction effectively suppresses Taylor-rising behavior, due to the increased contact angle, density, and decreased surface tension. Without addition of ATP, untriggered RCA reaction is favorable for Taylor rising, resulting in a significant height. With this proposed method, visual sensitive detection of ATP without the aid of other instruments is realized with only a 5 μL droplet, which has good selectivity and a low detection limit (17 nM). Importantly, this visual method provides a promising POCT tool for user-friendly molecular diagnostics.

Excessive use of pesticides in modern agriculture results in large amounts of pesticide residues in agricultural production, greatly threatening human health. Herein, novel two-dimensional leaf-like zeolitic imidazolate framework-L decorated with multi-walled carbon nanotubes (MWCNTs/ZIF-L) was prepared by a facile solvent way and exploited as electrode material for sensitive electrochemical sensing of thiabendazole (TBZ). Two-dimensional ZIF-L presents high surface area, large pore volume, and abundant active sites, which exhibits high enrichment ability towards TBZ molecules, while the MWCNTs interspersed on ZIF-L can prominently enhance the electron transport capability and improve the electrocatalytic activity for TBZ oxidation. Due to the intriguing synergy between the components, the MWCNTs/ZIF-L-based electrochemical sensor reveals a limit of detection (LOD) of 6.0 nmol·L−1, which is lower than that reported in most literatures. Additionally, satisfactory reproducibility and repeatability, long-term stability, and excellent selectivity are acquired. The proposed method was also applied for the detection of TBZ in apple and orange samples with acceptable recoveries.

Aim Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). Method This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. Results In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. Conclusions The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. Trial registration ClinicalTrials.gov identifier: NCT01677559 .

Palladium/BuAd2P efficiently catalyzed the direct α-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue (12) shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. Docking results of compound 12 also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).

This study aims to determine the effects and mechanism of action of muscone on the biological activity of the gastric cancer cell lines SGC‐7901 and MGC‐803 (proliferation, apoptosis, invasion, and migration) in vitro. An optimal muscone concentration was determined using MTT and cell apoptosis tests. The SGC‐7901 and MGC‐803 cells were divided into five groups: normal control, muscone, miRNA, muscone + miRNA, and muscone + miRNA inhibitor. Cell proliferation rate, apoptosis rate, cell cycle phase distribution, number of invading cells, and wound healing rate were compared among the five groups using MTT, flow cytometry, transwell, and wound healing assays. Relative expression levels of the proteins PI3K, AKT, P21, c‐Myc, MMP‐2, and MMP‐9 were measured by Western blot. Compared with the control group, the groups treated with muscone and miRNA showed significantly lower cell proliferation rate, number of invading cells, and wound healing rate (p, Muscone suppressed SGC‐7901 biological activities via regulation of miRNA‐145 in vitro.

The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of N-(hetero)aryl analogues (1-32) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the N-aryl-huperzine A (N-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in in vitro experiments. Three arylated huperzine A analogues (14, 19, and 30) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue (30) displayed the most potent AChE inhibition activity, with an IC50 value of 1.5 μM, which was 7.6-fold more active than HPA. Compound 30 also exhibited better neuroprotective activity for H2O2-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound 30 showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development.

It is imperative to develop methods for quantifying and imaging hypochlorous acid/hypochlorite (HOCl/ClO−) in living systems to clarify its roles in physiological and pathological processes and optimize therapeutic interventions for related diseases. Herein, we develop a ratiometric semiconducting polymer dot (Pdot)-based fluorescent probe with dual-emission at blue and green regions, PFO–PFPV Pdot, which is prepared from two fluorescent conjugated polymers including poly(9,9-dioctylfluorenyl-2,7-diyl) (PFO) and poly[(9,9-dioctyl-2,7-divinylene-fluorenylene)-alt-{2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylene}] (PFPV), for detecting and imaging HOCl in living cells. The presence of HOCl can selectively oxidize PFPV components in Pdots and the oxidation reaction can be enhanced by UV irradiation, which interrupts the fluorescence resonance energy transfer (FRET) from PFO to PFPV and results in the fluorescence quenching of PFPV at green emission region and recovery of PFO at blue emission region. On the basis of the ratios of fluorescence intensities at PFPV and PFO as a function of HOCl concentrations, a ratiometric fluorimetry for HOCl detection with a low detection limit of 56.8 nM is proposed. Furthermore, the developed fluorescent probe is also used for ratiometric fluorescence imaging of exogenous and endogenous HOCl in RAW264.7 cells with satisfactory results. The developed PFO–PFPV Pdots show high specificity and sensitivity, low cytotoxicity, and good biocompatibility for HOCl detection.

Genome replication is a fundamental requirement for the proliferation of all cells. Throughout the domains of life, conserved DNA replication initiation proteins assemble at specific chromosomal loci termed replication origins and direct loading of replicative helicases (1). Despite decades of study on bacterial replication, the diversity of bacterial chromosome origin architecture has confounded the search for molecular mechanisms directing the initiation process. Recently a basal system for opening a bacterial chromosome origin (oriC) was proposed (2). In the model organism Bacillus subtilis, a pair of double-stranded DNA (dsDNA) binding sites (DnaA-boxes) guide the replication initiator DnaA onto adjacent single-stranded DNA (ssDNA) binding motifs (DnaA-trios) where the protein assembles into an oligomer that stretches DNA to promote origin unwinding. We report here that these core elements are predicted to be present in the majority of bacterial chromosome origins. Moreover, we find that the principle activities of the origin unwinding system are conserved in vitro and in vivo. The results suggest that this basal mechanism for oriC unwinding is broadly functionally conserved and therefore may represent an ancestral system to open bacterial chromosome origins.

A label-free and sensitive electrochemical biosensing strategy for a hepatocellular carcinoma biomarker of miRNA-122 has been proposed based on hybridization induced ion-barrier effect on the electroactive sensing interface. First, a bifunctional electroactive electrode with the nanocomposite of Prussian blue (PB) and gold nanoparticles (AuNPs) was prepared through a two-step electrodeposition process. The PB endows the electrode excellent K+-dependent voltammetric signal and the AuNPs act as the matrix for the self-assembly immobilization of the thiolated probe DNA. Upon specific hybridization of probe DNA with the target miRNA-122, the formed double duplex induced the ion-barrier effect, which blocked the diffusion of the K+ from the bulk solution to the electrode surface. As a result, the voltammetric signal of the PB on the electrode was surpressed, and thus the target miRNA-122 was monitored. The sensing assay showed that the miRNA-122 could be analyzed in the concentration range from 0.1 fmol/L to 1.0 nmol/L, with a detection limit of 0.021 fmol/L. The practical applicability of the biosensor was also verified by the spiking serum assay.

Receptor-like kinases (RLKs) are essential for plant abiotic stress responses. Methylglyoxal (MG) is a cellular metabolite that is often considered to be a stress signal molecule. However, limited information is available about the relationship between RLKs and MG. Here, we addressed the function of a receptor-like kinase, OsASLRK, in the MG response and content in rice. A typical MG-responsive element (AAAAAAAA) exists in the promoter region of the OsASLRK gene. RTqPCR analysis indicated that the transcript level of OsASLRK was significantly increased by exogenous MG in a time- and dosage-dependent fashion. GUS staining also confirmed that the expression of OsASLRK in rice root was enhanced by exogenous MG treatment. Genetic analysis suggested that the Osaslrk mutant displays increased sensitivity to MG and it showed higher endogenous MG content under exogenous MG treatments, while OsASLRK-overexpressing rice plants showed the opposite phenotypes. Diaminobenzidine (DAB) staining, scavenging enzyme activities and GSH content assays indicate that OsASLRK regulates MG sensitivity and content via the elevation of antioxidative enzyme activities and alleviation of membrane damage. Therefore, our results provide new evidence illustrating the roles that receptor-like kinase OsASLRK plays in MG regulation in rice.

PURPOSE: Patients with triple negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin, and to identify molecular alterations and/or immune gene signatures predicting pCR. EXPERIMENTAL DESIGN: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles. RESULTS: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend towards higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80, versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteosome were upregulated in pre-treatment samples from patients who achieved pCR. CONCLUSIONS: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR. TRIAL REGISTRATION: Clinical trial information: NCT02124902, Registered 24 April 2014, & NCT02547987, Registered 10 September 2015.

Amines are widely employed as additives for improving the performance of metal halide perovskite optoelectronic devices. However, amines are well-known for their high chemical reactivity, the impact of which has yet to receive enough attention from the perovskite light-emitting diode community. Here, by investigating an unusual positive aging effect of CH3NH3I/CsI/PbI2 precursor solutions as an example, we reveal that amines gradually undergo N-formylation in perovskite precursors over time. This reaction is initialized by hydrolysis of dimethylformamide in the acidic chemical environment. Further investigations suggest that the reaction products collectively impact perovskite crystallization and eventually lead to significantly enhanced external quantum efficiency values, increasing from similar to 2% for fresh solutions to greater than or similar to 12% for aged ones. While this case study provides a positive aging effect, a negative aging effect is possible in other perovksite systems. Our findings pave the way for more reliable and reproducible device fabrication and call for further attention to underlying chemical reactions within the perovskite inks once amine additives are included. Funding Agencies|ERCEuropean Research Council (ERC)European Commission [717026]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [SFO-Mat-LiU 2009-00971]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [51472164, 62005126]; 1000 Talents Program for Young Scientists of China; Shenzhen Peacock Plan [KQTD2016053112042971]; Educational Commission of Guangdong Province [2015KGJHZ006]; Research Foundation-Flanders (FWO)FWO [12Y7221N]

Two new premyrsinane-type diterpenes (2 and 3) as diastereomers were synthesized from lathyrane-type diterpene euphorbia factor L3 (1) for the first time via an efficient Fe(acac)3-catalyzed skeleton conversion process. This conversion features a biogenetically inspired strategy that relies on a concise reductive olefin coupling involving intramolecular Michael addition with free radicals. The structures of 2 and 3 were elucidated by a combination of the interpretation of their spectroscopic data and single-crystal X-ray diffraction analysis. The premyrsinane diterpenes 2 and 3 exhibited cytotoxic activity against the 4T1 breast cancer cell line, while the parent compound euphorbia factor L3 (1) was inactive. The current results not only confirmed the biogenetic relationship between lathyranes and premyrsinanes for the first time but also suggested a novel method for the preparation of naturally rare premyrsinane diterpenes with high bioactivity from the more abundant natural lathyrane diterpenes.

Purpose Epoxy resin (EP) is a kind of thermosetting resin, and its application is usually limited by poor toughness. In this case, a type of new flexible chain blocking hyperbranched polyester (HBP) was designed and synthesized. The purpose of this study is to enhance the toughness and dielectric properties of EP. Design/methodology/approach P-toluene sulfonic acid was used as the catalyst, with dimethy propionic acid as the branch unit and pentaerythritol as the core in the experiment. Then, n-hexanoic acid and n-caprylic acid were, respectively, put to gain HBP with a n-hexanoic acid and n-caprylic acid capped structure. The microstructure, mechanical properties, insulation properties and dielectric properties of the composite were characterized for the purpose of finding the appropriate proportion of HBP. Findings HBP enhanced the toughness of epoxy-cured products by interpenetrating polymer network structure between the flexible chain of HBP and the EP molecular chain. Meanwhile, HBP reduced the ε and tgδ of the epoxy anhydride-cured product by reducing the number of polar groups per unit volume of the EP through free volumes. Research limitations/implications Yet EP is a kind of thermosetting resin, which is widely used in coating, aerospace, electronics, polymer composites and military fields, but it is usually limited by poor toughness. In a word, it is an urgent priority to develop new EP with better toughness and mechanical properties. Originality/value At present, HBP has been applied as a new kind of toughening strategy and as a modifier for EP. According to the toughening mechanism of HBP modified EP, the free volume of HBP creates a space for the EP molecule to move around when loaded. Moreover, the free volume could cause the dielectric constant of EP to diminish by reducing the content of polarizable groups. Meanwhile, the addition of HBP with flexible chains grafted to the EP could develop an interpenetrating network structure, thus further enhancing the toughness of EP

A novel oxygen reduction reaction (ORR) electrocatalyst silver@platinum-cobalt-rGO nanoflower (Ag@PtCo-rGO NFs) is prepared by hydrothermal reduction method. The formation of silver chloride likes elm leaf microstructure in the reaction process, performing as a template. The Ag@PtCo-rGO NFs exhibit excellent electrocatalytic activity, whose specific activity is 9 times higher than that of commercial Pt/C. More importantly, Ag@PtCo-rGO NFs demonstrate excellent durability than JM Pt/C for ORR in acid media, as evidenced by accelerated durability test after 40,000 cycles. These excellent performances can be attributed to the special structure, atomic steps and synergistic effect between Pt, Ag and Co. The density functional theory calculation shows that Ag@PtCo has the best activity, which is related to the transition state for O–O bond. This work proposes a promising pathway for the synthesis of surfactant-free nanoflowers structure catalysts with high catalytic performance and low cost.

For the study, we prepared a low grain boundary three-dimensional CH3NH3PbI3 crystal (3D-MAPbI3) on TiO2 nanoarrays by inhibition of ammonium iodide and discussed the formation mechanism of the crystal. Based on the 3D-MAPbI3 crystal, solar cells showed modified performance with a power conversion efficiency (PCE) of up to 19.3%, which increases by 36.8% in contrast to the counterparts. We studied the internal photocurrent conversion process. The highest external quantum efficiency is up to 92%, and the electron injection efficiency is remarkably facilitated where the injection time decreases by 37.8% compared to the control group. In addition, based on 3D-MAPbI3, solar cells showed excellent air stability, which possesses 78.3% of the initial PCE, even though they were exposed to air for 30 days. Our results demonstrate a promising approach for the fabrication of perovskite solar cells with high efficiency and stability.

Screening for early‐stage disease is vital for reducing colorectal cancer (CRC)‐related mortality. Methylation of circulating tumor DNA has been previously used for various types of cancer screening. A novel cell‐free DNA (cfDNA) methylation‐based model which can improve the early detection of CRC is warranted. For our study, we collected 313 tissue and 577 plasma samples from patients with CRC, advanced adenoma (AA), non‐AA and healthy controls. After quality control, 187 tissue DNA samples (91 non‐malignant tissue from CRC patients, 26 AA and 70 CRC) and 489 plasma cfDNA samples were selected for targeted DNA methylation sequencing. We further developed a cfDNA methylation model based on 11 methylation biomarkers for CRC detection in the training cohort (area under curve [AUC] = 0.90 (0.85–0.94]) and verified the model in the validation cohort (AUC = 0.92 [0.88–0.96]). The cfDNA methylation model robustly detected patients pre‐diagnosed with early‐stage CRC (AUC = 0.90 [0.86–0.95]) or AA (AUC = 0.85 [0.78–0.91]). Here we established and validated a non‐invasive cfDNA methylation model based on 11 DNA methylation biomarkers for the detection of early‐stage CRC and AA. The utilization of the model in clinical practice may contribute to the early diagnosis of CRC., Cell‐free DNA (cfDNA) methylation is promising for colorectal cancer (CRC) screening. In this study, after DNA methylation sequencing of tissue and plasma samples, we established a cfDNA methylation model based on 11 DNA methylation biomarkers for the detection of early‐stage CRC and advanced adenoma. The utilization of the model may contribute to the non‐invasive early diagnosis of CRC.

Alzheimer’s disease (AD) is associated with high incidence of cardiovascular events but the mechanism remains elusive. Our previous study reveals a tight correlation between cardiac dysfunction and low mitochondrial aldehyde dehydrogenase (ALDH2) activity in elderly AD patients. In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD. Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice. Cognitive function, cardiac contractile, and morphological properties were assessed. We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test, myocardial ultrastructural, geometric (cardiac atrophy, interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies along with oxidative stress, apoptosis, and inflammation in myocardium. ALDH2 transgene significantly attenuated or mitigated these anomalies. We also noted the markedly elevated levels of lipid peroxidation, the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4), the transcriptional regulator for ACLS4 special protein 1 (SP1) and ferroptosis, evidenced by elevated NCOA4, decreased GPx4, and SLC7A11 in myocardium of APP/PS1 mutant mice; these effects were nullified by ALDH2 transgene. In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro, application of Aβ (20 μM) decreased cell survival, compromised cardiomyocyte contractile function, and induced lipid peroxidation; ALDH2 transgene or activator Alda-1 rescued Aβ-induced deteriorating effects. ALDH2-induced protection against Aβ-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid (TA) or the ACSL4 inhibitor triacsin C (TC), and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid (5-HETE) or the ferroptosis inducer erastin. These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis.

Osteoporosis is a skeletal condition that is characterized by decreasing bone density and deteriorating bone mass. The plant-based phytoconstituent such as geraniin possesses better therapeutic potentials in biomedical field. In the current experimental study, we planned to scrutinize the therapeutic potential of geraniin against ovariectomy (OVX)-induced osteoporosis in rats and find the possible mechanism. Healthy Sprague Dawley rats were randomized into six groups and subjected to geraniin and alendronate (ALN) treatment for 10 weeks. Body weight, uterus, femur weight, bone biochemical, bone turnover markers, inflammatory cytokine, calcium, phosphorus, vitamin D (Vit D), urine, hormones, and antioxidant level were estimated. Geraniin significantly (p < .001) reduced the level of bone turnover markers including beta-CrossLaps (β-CTx), ALN, osteocalcin (OC), alkaline phosphatase (ALP), and bone Gla protein (BGP); reduced the biomechanical parameters including maximum load, energy, stiffness, maximum stress, and Young's modulus; reduced the level of calcium (Ca) and phosphorus (P); and increased the level of vitamin D (Vit D) as compared with OVX-induced osteoporosis rats. Geraniin increased the level of bone structure parameters, namely bone mineral density, bone mineral content, tissue mineral density, bone volume fraction, and trabecular number; increased the level of osteoprotegerin (OPG) and OPG/RANKL; and reduced the level of receptor activator of nuclear factor kappa-Β ligand (RANKL). Geraniin significantly (p < .001) increased the level of glutathione (GSH) and reduced the level of malonaldehyde (MDA) in the liver, intestine, and bone of OVX-induced osteoporosis rats. Geraniin significantly (p < .001) decreased the level of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) pro-inflammatory cytokines. We also argue that geraniin could be an excellent candidate to treat and control bone-related disease or disorders.

Drug resistance, including multidrug resistance resulting from different defensive mechanisms in cancer cells, is the leading cause of the failure of the cancer therapy, posing an urgent need to develop more effective anticancer agents. Chalcones, widely distributed in nature, could act on diverse enzymes and receptors in cancer cells. Accordingly, chalcone derivatives possess potent activity against various cancers, including drug-resistant, even multidrug-resistant cancer. This review outlines the recent development of chalcone derivatives with potential activity against drug-resistant cancers covering articles published between 2010 and 2020 so as to facilitate further rational design of more effective candidates.

Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-09.

Poly(ethylene terephthalate) (PET) is one of the most commonly used plastics worldwide and its accumulation in the environment is a global problem. PETase from Ideonella sakaiensis 201-F6 was reported to exhibit higher hydrolytic activity and specificity for PET than other enzymes at ambient temperature. Enzymatic degradation of PET using PETase provides an attractive approach for plastic degradation and recycling. In this work, extracellular PETase was achieved by Escherichia coli BL21 using a Sec-dependent translocation signal peptide, pelB, for secretion. Furthermore, engineering of the pelB through random mutagenesis and screening was performed to improve the secretion efficiency of PETase. Evolved pelB enabled higher PETase secretion by up to 1.7-fold. The improved secretion of PETase led to more efficient hydrolysis of the PET model compound, bis (2-hydroxyethyl) terephthalic acid (BHET), PET powder, and PET film. Our study presents the first example of the increasing secretion of PETase by an engineered signal peptide, providing a promising approach to obtain extracellular PETase for efficient enzymatic degradation of PET.

In the present study, we investigate the surface acid–base properties of anatase TiO2 nanomaterials with dominant {101} and {001} facets via methanol titrations. Two anatase nanoparticles, TiO2(101...

Dihydromyricetin (DMY), an important flavanone found in Ampelopsis grossedentata, plays a protective role in liver injury. Our previous research found that DMY protected L02 cells against hepatotoxicity caused by emodin. In this study, serum, urine, and liver samples from rats were systematically used for biochemical analysis, pathological observation, and nontargeted metabolomics to evaluate the toxicity of emodin and DMY intervention. After oral administration of DMY, DMY may alleviate liver injury by improving liver metabolism. Approximately, 8 of 15 metabolites in rat urine and serum were significantly regulated by DMY. Metabolic pathway analysis showed that glutathione metabolism, pyrimidine metabolism, and tryptophan metabolism were the most affected pathways, and 18 proteins were predicted to be potential targets of DMY during the alleviation of liver injury induced by emodin. This research is of great significance in confirming the liver-protective effect of DMY, especially during acute liver injury caused by traditional Chinese medicine.

Oxidative stress has always been a hot topic in poultry science. However, studies concerning the effects of redox status and glucose metabolism induced by hydrogen peroxide (H2O2) in the breast muscle of broilers have been rarely reported. This study was aimed to evaluate the impact of intraperitoneal injection of H2O2 on oxidative damage and glycolysis metabolism of breast muscle in broilers. We also explored the activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway to provide possible mechanism of the redox imbalance. Briefly, a total of 320 one-day-old Arbor Acres chicks were randomly divided into 5 treatments with 8 replicates of 8 birds each (noninjected control, 0.75% saline-injected, 2.5, 5.0, and 10.0% H2O2-injected treatments). Saline group was intraperitoneally injected with physiological saline (0.75%) and H2O2 groups received an intraperitoneal injection of H2O2. The dosage of the injection was 1.0 mL/kg BW. All birds in the saline and H2O2 groups were injected on days 16 and 37 of the experimental period. At 42 d of age, 40 birds (8 cages per group and one chicken per cage) were selected to be stunned electrically (50 V, alternating current, 400 Hz for 5 s each one), and then immediately slaughtered via exsanguination. The results showed that broilers in the H2O2 injection group linearly exhibited higher contents of reactive oxygen species, carbonyl and malondialdehyde, and lower total antioxidant capacity and glutathione peroxidase activities. With the content of H2O2 increased, the H2O2 groups linearly downregulated the mRNA expressions of GPX, CAT, HMOX1, NQO1, and Nrf2 and its downstream target genes. In addition, H2O2 increased serum activities of creatine kinase and lactate dehydrogenase. Meanwhile, in the pectoral muscle, the glycogen content was linearly decreased, and the lactate content was linearly increased in muscle of broilers injected with H2O2. In addition, the activities of glycolytic enzymes including pyruvate kinase, hexokinase, and lactate dehydrogenase were linearly increased after exposure to H2O2. In conclusion, H2O2 injection could impair antioxidant status and enhance anaerobic metabolism of breast muscle in broilers.

To reveal the underlying relationships between Chinese medicine (CM) syndromes and ultrafiltration (UF) in the treatment of heart failure based on a metabonomic approach. Seventeen acute decompensated heart failure (ADHF) patients were enrolled, and their CM syndromes before and after UF were collected. In addition, their venous plasma collected before and after UF was used for liquid chromatographmass spectrometer-based metabonomic analysis. Both reversed phase liquid chromatography and hydrophilic interaction liquid chromatography were used to analyze the plasma samples. Partial least-squares to latent structure-discriminant analyses were used for data analysis. An obvious difference was observed pre- and post-treatment. A total of 17 potential biomarkers associating with alterd syndromes with UF including hypoxanthine, 1-methylhistidine, phytosphingosine, O-decanoyl-R-carnitine, etc. were screened out, showing a significant change after UF. The major adjusted metabolic pathways were purine metabolism, histidine metabolism, leucine and isoleucine metabolism, arginine and proline metabolism, carnitine shuttle, sphingolipid metabolism and phospholipid metabolism. Metabonomic approach is a useful tool to identify potential biomarkers of altered syndromes link to UF and could provide a theoretical basis for further research on the therapeutic mechanism of UF combined with CM.

The construction of organic solar cells with stacked structures by the sequential deposition (SD) of donor and acceptor films has great potential in industrial production, as it demonstrates little dependence on the ratio of donor and acceptor materials, solvents, and additives. Herein, we present an eco-friendly solvent protection (ESP) method for the fabrication of high-performance OSCs with stacked structures. Several non-aromatic and non-halogenated solvents are employed as protective agents to build SD devices with a configuration of indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS Clevios P VP Al 4083)/donor/protective solvent/acceptor/perylene diimide functionalized with amino N-oxide (PDINO)/Al, which shows that n-octane is the optimal choice for SD devices. Nine different SD systems including the fullerene and nonfullerene ones present comparable photovoltaic performance to their BC counterparts, which proves the universality of this ESP method. Significantly, the device of ITO/PEDOT:PSS/D18/N3/PDINO/Al with n-octane as the protective solvent achieves a maximum PCE of 17.52%, which is the record efficiency of SD devices. Furthermore, a protective factor (δ) is proposed to demonstrate the quantitative relationship between δ and PCE after experimental and theoretical investigation, which presents an idea to understand the mechanism and provides a guideline for solvent choices.

This study describes an improved alkaline fusion technique for the Re–Os dating of molybdenite. The molybdenite sample was digested in a zirconium crucible with NaOH and carbonized flour at 700 °C. The flour can reduce Os from a high oxidation state to a lower oxidation state during the high-temperature digestion so that isotope equilibration can be reached between the spike and the sample. Less amount of NaOH was used compared with the previously reported technique, lowering the procedure blank. Rhenium was separated by kinetic absorption with an anion exchange resin, and Os was purified by distillation with aqua regia and H2O2. Both Re and Os isotope compositions were measured via inductively coupled plasma mass spectrometry. The results obtained for the molybdenite reference material, JDC, were in good agreement with certified values, demonstrating that the proposed method is efficient for the Re–Os dating of molybdenite. Compared with Carius tube and high-pressure asher sealed acid digestion methods, the improved alkaline fusion method yields comparable Os blanks but has a more simple, quick, and secure procedure.

Hypercrosslinked polymers HCP-DMF and HCP-DMF-SO3H containing abundant and flexible DMF moieties were designed and synthesized. Benefitting from the solvation microenvironment provided by the pseudo-DMF moities, the polar HCPs manifested outstanding performances in the conversions of NaN3 to benzylic azides and 1,2,3-triazoles in EtOH (95%), respectively, avoiding the use of risky DMF and improving the separation processes of the products.

A Metal-Organic Framework (MOFs) with large surface area, exposed active site, excellent catalytic performance and high chemical stability has been used as an artificial enzyme and designed for nonenzymatic electrochemical sensors. Here, a strategy of using an enhanced electrochemical sensing platform for the detection of nitic oxide (NO) and hydrogen peroxide (H2O2) was designed via a nano-metalloporphyrinic metal-organic framework (NporMOF(Fe)) as an electrode material. By taking advantage of the small size, high surface area and exposed Fe active site, the obtained NporMOF(Fe) displays excellent electrocatalytic activity toward NO and H2O2. The NporMOF(Fe) modified electrode shows high sensing ability toward the in situ generated NO in NO2- containing phosphate buffer (PB) solution with a wide linear detection range of 5 μM to 200 μM and a very low detection limit of 1.3 μM. Moreover, NporMOF(Fe) exhibits high electrocatalytic activity toward the reduction of H2O2 and the practical detection of H2O2 released from HeLa cells. Furthermore, the NporMOF(Fe) modified electrode shows excellent selectivity toward the detection of NO and H2O2 in the presence of other physiologically important analytes. This method shows excellent biosensing performance, implying the universal applicability of MOFs-based artificial nanozymes for biosensors and the potential application for third generation biosensors.

A butyl acetate solution of bisphenol S (BPS) was proved to be able to replace hazardous halogenated solvents in the transformation of indoles. Measurement with Kamlet–Taft solvatochromic parameters disclosed that the polarity of the BPS-containing butyl acetate was enhanced greatly. The protocol not only conferred a convenient way to minimize the use of halogenated solvents in the synthesis of indole derivatives, but also enabled successful recycling of both the butyl acetate solvent and BPS additive, strengthening the greenness of the reaction systems.

A pair of carboxy-cyclobutane isomers were synthesized stereoselectively using a method that combined reversible amide bond formation and self-assembly of coordination polymers (CPs) via solid-state photochemical [2 + 2] cycloaddition reactions. Amide bond formation occurred by the condensation of amino and carboxy groups to prepare a pyridine-amide ligand, while pyridine-amide CPs were constructed by the self-assembly of metal ions, pyridine-amide, and auxiliary ligands for the solid-state [2 + 2] photodimerization during the second step. The pyridine-amide ligand underwent the [2 + 2] cycloaddition reaction in 2D CPs to generate amide-cyclobutane derivatives stereoselectively that were afforded by removing metal ions and auxiliary ligands under alkaline conditions. The carboxy-cyclobutane isomers were successfully synthesized by the hydrolysis of the amide-cyclobutane derivatives. Moreover, the second amide-cyclobutane derivative and carboxy-cyclobutane derivative were obtained stereoselectively via regulating the reaction site of [2 + 2] cycloaddition by introducing a substituent group in the auxiliary ligand.

In the research of carbon dots (CDs) containing various nitrogen sources, it was first found that urea/citric acid-CDs showed a selective discolouration reaction with sulphide ions. Therefore, by optimizing various synthesis and detection conditions of the CDs determining sulfur ions, such as the raw material ratio, temperature, time, pH, and oxidation atmosphere in the CD synthesis, a discolour CD-probe method for trace-level sulphide ions was developed. The method is environmentally friendly, shows two linear-response ranges in 0.050-1.0 mg L-1 (A = -0.0827c + 0.8366) and 1.0-15 mg L-1 S2- (A = -0.0209c + 0.7587) and can be used for the high and low concentration quantification of sulphide in various wastewaters. Subsequently, in order to realize the separation and detection of sulphide ions in wastewaters or rich- and barren-liquids containing N-methyldiethanolamine and other substances in desulphurizing solutions, an automatic pretreatment system was also established.

High-entropy materials have gained extensive attention owing to their unique structural characteristics and outstanding properties. The synthesis of high-entropy compounds, particularly high-entropy metal phosphides, has been seldom reported because of the incompatibility between different metals and non-metals. Herein, we propose a one-step low temperature sol–gel strategy to overcome the incompatibility and synthesize high-entropy metal phosphide (HEMP) NiCoFeMnCrP nanoparticles on a carbon matrix. Due to the synergistic effect among the metal elements, NiCoFeMnCrP exhibits supernormal catalytic activities for the oxygen evolution reaction (OER), hydrogen evolution reaction (HER) and overall water splitting. The fact that the overpotentials for the OER and HER decrease with the increase of the metal species number demonstrates that the realization of high entropy has great effects on performance enhancement. Our work provides a facile and viable synthesis strategy for preparing high entropy compounds which would offer great potential in energy and electrocatalysis applications by entropy engineering.

Enzyme-based electrochemical biosensors have been widely employed for analyte detection for several years. However, for wide application, there are many challenges to overcome, such as the sensitivity of the catalytic activity, and the reproducibility and stability of enzymes. In this work, an enzyme-free sensing strategy based on two-dimensional (2D) metal-organic frameworks (MOFs) as photosensitizers and singlet-oxygen (1O2) as the oxidant has been designed via photocatalysis and electrochemical analysis. To be specific, MOF sheets (Zn-ZnMOF) were prepared with Zn as the node and zinc(ii)tetraphenylporphyrin (TCPP(Zn)) as the ligand, which could generate 1O2 from air under light illumination, and sequentially the generated 1O2 could oxidize analytes to form their oxidation state which could be detected and reduced on the electrode, completing a redox cycle and amplifying electrochemical signals. Thanks to the morphology and superior quantum yield of 1O2 of the Zn-ZnMOF, this method could overcome the limitation of enzymes and afford selective detection, such as of hydroquinone with a detection limit of 0.8 μM in 0.1 M PBS (pH = 7.4). Furthermore, the method does not require additional reactive reagents but only with air and on/off light switching. Thirdly, the method detects the target without washing and enzyme-labelled. With these merits, this work provides a new platform for MOFs as photosensitizers for electrochemical sensors and further development of sensitive, selective, and stable electroanalytical devices for bio-application.

Background 64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1–4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. Results We found that the presence of pyridyl groups significantly increases 64Cu labeling conversion yield, with DOTA-2Py, −3Py and -4Py quantitatively complexing 64Cu at room temperature within 5 min (1 × 10− 4 M). [64Cu]Cu-DOTA-xPy (x = 2–4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64Cu complexes. DOTA-xPy (x = 1–3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [64Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1–3.7 nM) towards the melanocortin 1 receptor. Conclusion DOTA-xPy (x = 1–3) are promising chelators for 64Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.

Biofilm infections present an enormous challenge in today's healthcare settings. Currently, pH-switchable antibacterial agents are being developed to eradicate biofilms. However, most pH-switchable antibacterial agents are less lethal to planktonic bacteria under neutral conditions, and cannot prevent the dispersed bacteria from seeding acute infection again. Herein, this work reports the applications of semiconducting polymer dots (Pdots) with a double adhesion mechanism in imaging and inhibiting bacteria inside (weak acidic conditions) and outside (neutral conditions) biofilms. Clew-like Pdots were prepared by covalently linking phenylboronic acid (PBA) and pH-responsive naphthalimide (NA) ramification in semiconducting polymers. Under neutral conditions, the Pdots combined with bacteria through the formation of boronate esters between PBA and diols. Under weakly acidic conditions, the partial borate bond fractured, and the Pdots adhered onto the bacterial surface through the positively charged NA in Pdots. Furthermore, the Pdots display negligible toxicity to mammalian cells and tissues. More importantly, the Pdots can selectively damage the bacterial membrane and inhibit bacteria in vivo. This work highlights the feasibility of using semiconducting Pdots to image and inhibit bacteria inside and outside biofilms, which represents a highly effective strategy to cope with biofilm infections.

In this study, a novel reaction-based A-A-A (acceptor-acceptor-acceptor) type two-photon fluorescent probe, BTC, is prepared using the benzothiadiazole (BTD) scaffold as the two-photon fluorophore and electron-accepting centre. Two β-chlorovinyl aldehyde moieties are symmetrically connected to both ends of the BTD scaffold and act as reaction groups to recognize SO2 and quenching groups to make the dis-activated probe stay at off-state due to their weak electron-withdrawing effect. In the presence of SO2 derivatives, the aldehyde groups are consumed through aldehyde addition, resulting in the activation of intramolecular charge transfer (ICT) processes and therefore recovering the fluorescence of the probe. The designed probe shows excellent two-photon properties including large two-photon absorption cross-sections (TPA) of 91 GM and photostability. Beyond these, the BTC probe exhibits a fast response to SO2 within 30 s, high specificity without foreign interference and a broad detection range from 500 nM to 120 μM with a detection limit of 190 nM. The designed fluorescent probe is further applied to the two-photon imaging of exogenous and endogenous SO2 derivatives under different physiological processes in HeLa cells and zebrafish with satisfactory results. We believe that the proposed design strategy can be extended to fabricate versatile BTD-based two-photon fluorescent probes through molecular engineering for further applications in bioassays and two-photon imaging.

Objective: This study was conducted to investigate the effects of dietary corn resistant starch (RS) on the intestinal morphology and barrier functions of broilers.Methods: A total of 320 one-day-old broilers were randomly allocated to 5 dietary treatments: one normal corn–soybean (NC) diet, one corn–soybean–based diet supplementation with 20% corn starch (CS), and 3 corn–soybean–based diets supplementation with 4%, 8%, and 12% corn resistant starch (RS) (identified as 4% RS, 8% RS, and 12% RS, respectively). Each group had eight replicates with eight broilers per replicate. After 21 days feeding, one bird with a body weight (BW) close to the average BW of their replicate was selected and slaughtered. The samples of duodenum, jejunum, ileum, caecum digesta, and blood were collected.Results: Birds fed 4% RS, 8% RS and 12% RS diets showed lower feed intake, BW gain, jejunal villus height (VH), duodenal crypt depth (CD), jejunal VH/CD ratio, duodenal goblet cell density as well as mucin1 mRNA expressions compared to the NC group, but showed higher concentrations of cecal acetic acid and butyric acid, percentage of jejunal proliferating cell nuclear antigen-positive cells and delta like canonical Notch ligand 4 (Dll4), and hes family bHLH transcription factor 1 mRNA expressions. However, there were no differences on the plasma diamine oxidase activity and D-lactic acid concentration among all groups.Conclusion: These findings suggested that RS could suppress intestinal morphology and barrier functions by activating Notch pathway and inhibiting the development of goblet cells, resulting in decreased mucins and tight junction mRNA expression.

Understanding the molecular responses of plant roots to the challenging environment contributes to engineering plants with improved stress tolerance. However, little has been done to understand rice (Oryza sativa L.) roots response to the toxic concentration of zinc (Zn) at the proteomic level. This study explored proteomic responses of young rice roots 5–6 days after sowing to 765 μM of Zn in a hydroponic set-up after 4-day exposure. Dye staining method and spectrophotometry were chosen for physiological response investigations. ICP-MS was used to determine metal content in rice seedlings. Two-dimensional gel electrophoresis was used for the proteomic study of root tissue. Elevated Zn reduced Mg translocation to the shoots and Mn uptake, decreased plant growth, and increased cell death of roots. Zn stimulated the biosynthesis of glutathione but decreased ROS and malondialdehyde levels. In total, 42 Zn-responsive proteins were identified. Proteins involved in redox regulation, defense response, sulfur metabolism, and proteolysis were induced, while those of energy production and cell wall biogenesis were decreased. Roots of O. sativa seedlings could tolerate certain Zn excess (765 μM Zn for 4 days) by stimulating nutrient recycling and glycolysis, and production of defensive metabolites and proteins to maintain ion and redox homeostasis. Besides, adenosylhomocysteinase (AHCY) down-regulation may contribute to balanced transmethylations, and methionine salvage pathway appears important for the adaptation to Zn. Our results provide some new insight into a complex metabolic response of rice roots to Zn stress, which is related to both stress and defense mechanisms.

Dysfunction of epidermal growth factor receptor (EGFR) signalling plays a critical role in the oncogenesis of non–small‐cell lung cancer (NSCLC). Here, we reported the natural product, licochalcone A, exhibited a profound anti‐tumour efficacy through directly targeting EGFR signalling. Licochalcone A inhibited in vitro cell growth, colony formation and in vivo tumour growth of either wild‐type (WT) or activating mutation EGFR‐expressed NSCLC cells. Licochalcone A bound with L858R single‐site mutation, exon 19 deletion, L858R/T790M mutation and WT EGFR ex vivo, and impaired EGFR kinase activity both in vitro and in NSCLC cells. The in silico docking study further indicated that licochalcone A interacted with both WT and mutant EGFRs. Moreover, licochalcone A induced apoptosis and decreased survivin protein robustly in NSCLC cells. Mechanistically, we found that treatment with licochalcone A translationally suppressed survivin through inhibiting EGFR downstream kinases ERK1/2 and Akt. Depletion of the translation initiation complex by eIF4E knockdown effectively inhibited survivin expression. In contrast, knockdown of 4E‐BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR‐targeted therapy.

La-doped strontium titanite (Sr0.9La0.1TiO3) is a promising candidate for n-type oxide thermoelectric materials. However, the ZT values of this material are low, leading to low conversion efficiency. Improvements in this efficiency are required. In this work, a high ZT value of 0.50 was obtained for Sr0.9La0.1TiO3 ceramic samples by adding 10 wt % Bi2O3 sintering aids and 20 wt % nanosized Ti powders to the matrix material. Although Ti was oxidized to TiO2 during the sintering process, nanoscale phase interfaces were beneficial for phonon scattering and thermal conductivity reduction. Nanosized metallic Bi and Bi2O3 particles were observed. These two factors played an important role in reducing the thermal conductivity from 2.5 W/(m K) at room temperature to 1.31 W/(m K) at 1073 K. Nanostructure control using nanosized metal powders as additives combined with the Bi2O3 sintering aid paves a way for enhancement of thermoelectric properties of oxide thermoelectric materials.