Design Principles of Quinone Redox Systems for Advanced Sulfide Solid-State Organic Lithium Metal Batteries.

The emergence of solid-state battery technology presents a potential solution to the dissolution challenges of high-capacity small molecule quinone redox systems. Nonetheless, the successful integration of argyrodite-type Li6PS5Cl, the most promising solid-state electrolyte system, and quinone redox systems remains elusive due to their inherent reactivity. Here, a library of quinone derivatives is selected as model electrode materials to ascertain the critical descriptors governing the (electro)chemical compatibility and subsequently the performances of Li6PS5Cl-based solid-state organic lithium metal batteries (LMBs). Compatibility is attained if the lowest unoccupied molecular orbital level of the quinone derivative is sufficiently higher than the highest occupied molecular orbital level of Li6PS5Cl. The energy difference is demonstrated to be critical in ensuring chemical compatibility during composite electrode preparation and enable high-efficiency operation of solid-state organic LMBs. Considering these findings, a general principle is proposed for the selection of quinone derivatives to be integrated with Li6PS5Cl, and two solid-state organic LMBs, based on 2,5-diamino-1,4-benzoquinone and 2,3,5,6-tetraamino-1,4-benzoquinone, are successfully developed and tested for the first time. Validating critical factors for the design of organic battery electrode materials is expected to pave the way for advancing the development of high-efficiency and long cycle life solid-state organic batteries based on sulfides electrolytes.

A dicarbonate solvent electrolyte for high performance 5 V-Class Lithium-based batteries.

Rechargeable lithium batteries using 5 V positive electrode materials can deliver considerably higher energy density as compared to state-of-the-art lithium-ion batteries. However, their development remains plagued by the lack of electrolytes with concurrent anodic stability and Li metal compatibility. Here we report a new electrolyte based on dimethyl 2,5-dioxahexanedioate solvent for 5 V-class batteries. Benefiting from the particular chemical structure, weak interaction with lithium cation and resultant peculiar solvation structure, the resulting electrolyte not only enables stable, dendrite-free lithium plating-stripping, but also displays anodic stability up to 5.2 V (vs. Li/Li+), in additive or co-solvent-free formulation, and at low salt concentration of 1 M. Consequently, the Li | |LiNi0.5Mn1.5O4 cells using the 1 M LiPF6 in 2,5-dioxahexanedioate based electrolyte retain >97% of the initial capacity after 250 cycles, outperforming the conventional carbonate-based electrolyte formulations, making this, and potentially other dicarbonate solvents promising for future Lithium-based battery practical explorations.

A case of achalasia associated with early esophageal cancer.

A 65-year-old man was admitted to our hospital complaining of reflux for more than 20 years. After endoscopy and barium-swallow examination, he was diagnosed with achalasia as well as a squamous cell carcinoma. Therefore, peroral endoscopic myotomy (POEM) combined with endoscopic submucosal dissection (ESD) was performed simultaneously. During the procedure, a mucosal erosion with a clear boundary was shown in the middle segment of the esophagus. ESD was first performed and the lesion was removed en-bloc. Subsequent POEM therapy was performed after marking the left esophageal wall 10cm above the cardia. After submucosal injection, the submucosal plane was created through a length 2cm longitudinal incision, then the muscle was cut a length of 10 cm into the esophagus and 2 cm below the cardia, and finally the incision was closed by clips. Pathological examination revealed high-grade intraepithelial neoplasia of squamous epithelium (carcinoma in situ) with a negative margin. The patient was recovered without complication four days after the procedure. The endoscopy showed perfect healing of the esophageal lesions during two-months follow-up , and the reflux symptom was resolved.

Tuning Intrinsic Spin Hall Effect in Platinum/Ferrimagnetic Insulator Heterostructure in Moderately Dirty Regime.

Studying the mechanisms of the spin Hall effect (SHE) is essential for the fundamental understanding of spintronic physics. By now, despite the intensive studies of SHE on heavy metal (HM)/metallic magnet heterostructures, the SHE on HM/ferrimagnetic insulator (FMI) heterostructures still remains elusive. Here, we study the mechanism of SHE in the Pt/Tm3Fe5O12 (TmIG) heterostructure. We first tune the crystallinity and resistivity of Pt by an annealing method, and then study the spin-orbit torque (SOT) in the tuned-Pt/TmIG devices. The SOT generation efficiency per unit electric field and spin Hall angle were obtained, which are insensitive to the annealing temperature. We further demonstrate that the intrinsic contribution in the moderately dirty regime is responsible for the SHE in our Pt/TmIG bilayer. Our study provides an important piece of information for the SHE in FMI-based spintronic physics.

Endoscopic mucosal resection with double band ligation versus endoscopic submucosal dissection for small rectal neuroendocrine tumors.

BACKGROUND: Endoscopic resection remains an effective method for the treatment of small rectal neuroendocrine tumors (NETs) (≤ 10 mm). Moreover, endoscopic mucosal resection (EMR) with double band ligation (EMR-dB), a simplified modification of EMR with band ligation, is an alternative strategy to remove small rectal NETs. AIM: To evaluate the feasibility and safety of EMR-dB for the treatment of small rectal NETs (≤ 10 mm). METHODS: A total of 50 patients with small rectal NETs, without regional lymph node enlargement or distant metastasis confirmed by endoscopic ultrasound, computerized tomography scan, or magnetic resonance imaging, were enrolled in the study from March 2021 to June 2022. These patients were randomly assigned into the EMR-dB (n = 25) group or endoscopic submucosal dissection (ESD) group (n = 25). The characteristics of the patients and tumors, procedure time, devices cost, complete resection rate, complications, and recurrence outcomes were analyzed. RESULTS: There were 25 patients (13 males, 12 females; age range 28-68 years old) in the EMR-dB group, and the ESD group contained 25 patients (15 males, 10 females; age range 25-70 years old). Both groups had similar lesion sizes (EMR-dB 4.53 ± 1.02 mm, ESD 5.140 ± 1.74 mm; P = 0.141) and resected lesion sizes(1.32 ± 0.52 cm vs 1.58 ± 0.84 cm; P = 0.269). Furthermore, the histological complete resection and en bloc resection rates were achieved in all patients (100% for each). In addition, there was no significant difference in the complication rate between the two groups. However, the procedure time was significantly shorter and the devices cost was significantly lower in the EMR-dB group. Besides, there was no recurrence in both groups during the follow-up period. CONCLUSION: The procedure time of EMR-dB was shorter compared with ESD, and both approaches showed a similar curative effect. Taken together, EMR-dB was a feasible and safe option for the treatment of small rectal NETs.

Chameleon Multienvironment Nanoreactors.

Nanoreactors consisting of hydrophilic porous SiO2 shells and amphiphilic copolymer cores have been prepared, which can easily self-tune their hydrophilic/hydrophobic balance depending on the environment and exhibit chameleon-like behavior. The accordingly obtained nanoparticles show excellent colloidal stability in a variety of solvents with different polarity. Most importantly, thanks to the assistance of the nitroxide radicals attached to the amphiphilic copolymers, the synthesized nanoreactors show high catalytic activity for model reactions in both polar and nonpolar environments and, more particularly, realize a high selectivity for the products resulting from the oxidation of benzyl alcohol in toluene.

Interleukin-22 Ameliorates Dextran Sulfate Sodium-Induced Colitis through the Upregulation of lncRNA-UCL to Accelerate Claudin-1 Expression via Sequestering miR-568 in Mice.

Background: Bioactive compound such as interleukin-22 (IL-22) treatment is regarded as a sufficient treatment for ulcerative colitis (UC). It has been found that long noncoding RNAs (lncRNAs) expressed in many inflammatory diseases, including UC. We aimed to verify the treatment effect of bioactive compounds including IL-22 and lncRNAs in UC on colitis mice. Methods: UC mice were induced using DSS, followed by IL-22 or PBS intraperitoneally (i.p.) injection. Then, the histopathological parameters of the mice were determined. Then, RNA sequencing was performed to screen the differential lncRNAs. Quantitative real-time PCR (qRT-PCR) and lentivirus identified lncRNA-Ulcerative Colitis lncRNA (lncRNA-UCL) were regarded as the molecular regulator of the colitis mice. The correlation with lncRNA-UCL and mmu-miR-568 was validated using RNA-pulldown. Meanwhile, claudin-1 was predicted and confirmed as the target molecule of mmu-miR-568 using dual-luciferase assay. Results: IL-22 could significantly improve the histopathological features and decrease proinflammatory cytokine production in UC mice induced by DSS. It also can stimulate intestinal epithelial cell (IEC) reproduction and prevention of apoptosis. lncRNA-UCL was significantly downregulated in UC mice caused by DSS, while IL-22 treatment effectively reversed this effect. In terms of mechanism, lncRNA-UCL regulates intestinal epithelial homeostasis by sequestering mmu-miR-568 and maintaining close integrated protein expression, such as claudin-1. Conclusions: We have demonstrated the incredible role of bioactive compound, such as IL-22, in alleviating DSS-induced colitis symptoms via enhancing lncRNA-UCL expression. It can be regulated using tight junction (TJ) protein.

Ethanol Alleviates Amyloid-ß-Induced Toxicity in an Alzheimer's Disease Model of Caenorhabiditis elegans.

Amyloid-ß, a hallmark of Alzheimer's disease, forms toxic intracellular oligomers and extracellular senile plaques resulting in neuronal toxicity. Ethanol is widely consumed worldwide. Moderate ethanol consumption has numerous benefits in humans. We found that ethanol could significantly extend the lifespan of Caenorhabiditis elegans in a previous study. Based on that study, we tested the effect of ethanol on Alzheimer's disease transgenic Caenorhabiditis elegans strain CL4176, which expresses amyloid-ß1-42 peptide in body wall muscle cells. Ethanol delayed paralysis and reduced amyloid-ß oligomers in Caenorhabiditis elegans worms of the CL4176 strain. Moreover, ethanol could induce the nuclear translocation of DAF-16 in the nematodes. However, in worms that were fed daf-16 RNAi bacteria, ethanol no longer delayed the paralysis. The qPCR assays showed that ethanol increases the expression of daf-16, hsf-1 and their common target genes- small heat shock protein genes. In addition, we also found that ethanol could increase lysosome mass in the CL4176 worms. In summary, our study indicated that ethanol attenuated amyloid-ß toxicity in the Alzheimer's disease model of Caenorhabiditis elegans via increasing the level of lysosomes to promote amyloid-ß degradation and upregulating the levels of small heat shock protein genes to reduce amyloid-ß aggregation.

Magnon Torque Transferred into a Magnetic Insulator through an Antiferromagnetic Insulator.

Electrical spin-orbit torque (SOT) in magnetic insulators (MI) has been intensively studied due to its advantages in spin-orbitronic devices with ultralow energy consumption. However, the magnon torque in the MIs, which has the potential to further lower the energy consumption, still remains elusive. In this work, we demonstrate the efficient magnon torque transferred into an MI through an antiferromagnetic insulator. By fabricating a Pt/NiO/Tm3Fe5O12 heterostructure with different NiO thicknesses, we have systematically investigated the evolution of the transferred magnon torque. We show that the magnon torque efficiency transferred through the NiO into the MI can retain a high value (∼50%), which is comparable to the previous report for the magnon torque transferred into the metallic magnet. Our study manifests the feasibility of realizing the pure magnon-based spin-orbitronic devices with ultralow energy consumption and high efficiency.

A Fluorescence Resonance Energy Transfer Probe Based on DNA-Modified Upconversion and Gold Nanoparticles for Detection of Lead Ions.

We report a new sensor for the specific detection of lead ions (Pb2+) in contaminated water based on fluorescence resonance energy transfer (FRET) between upconversion nanoparticles (UCNPs) as donors and gold nanoparticles (Au NPs) as receptors. The UCNPs modified with Pb2+ aptamers could bind to Au NPs, which were functionalized with complementary DNA through hybridization. The green fluorescence of UCNPs was quenched to a maximum rate of 80% due to the close proximity between the energy donor and the acceptor. In the presence of Pb2+, the FRET process was broken because Pb2+ induced the formation of G-quadruplexes from aptamers, resulting in unwound DNA duplexes and separated acceptors from donors. The fluorescence of UCNPs was restored, and the relative intensity had a significant linear correlation with Pb2+ concentration from 0 to 50 nM. The sensor had a detection limit as low as 4.1 nM in a buffer solution. More importantly, the sensor exhibited specific detection of Pb2+ in complex metal ions, demonstrating high selectivity in practical application. The developed FRET prober may open up a new insight into the specific detection of environmental pollution.

Platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: A meta-analysis.

BACKGROUND: This meta-analysis focuses on the controversial efficacy and safety of platelet-rich plasma (PRP) as compared with hyaluronic acid (HA) in the clinical treatment of knee osteoarthritis. We have attempted to provide an evidence-based medicine protocol for the conservative treatment of knee osteoarthritis. In addition, we included the latest relevant literature in this meta-analysis, and a staging study was conducted to compare the therapeutic effects of PRP and HA for knee osteoarthritis over different time periods. METHODS: An online computer search with "platelet-rich plasma" and "knee osteoarthritis" as search terms was conducted in the PubMed, EMBASE, and Cochrane Library databases. We conducted a quality assessment of the retrieved literature and extracted the following indicators: visual analog scale (VAS) score, subjective International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities (WOMAC) score, Knee Injury and Osteoarthritis Outcome Score (KOOS), and adverse events. RevMan5.3 software was used to determine the effect sizes, and indicators were compared across studies at three different time points from the administration of treatment. RESULTS: A total of 14 randomized controlled trials (RCTs) involving 1350 patients were included. Long-term VAS, IKDC, WOMAC-Pain, WOMAC-Stiffness, WOMAC-Physical Function, and WOMAC-Total scores at each time point were higher in the PRP group than in the HA group. There were no significant differences in the remaining indicators between the two groups. CONCLUSION: Compared with HA, PRP offers obvious advantages in the conservative treatment of knee osteoarthritis. Treatment with PRP can reduce long-term pain and improve knee joint function with no additional risks. Therefore, PRP can be widely used for the conservative treatment of knee osteoarthritis.

Development of a direct reverse-transcription quantitative PCR (dirRT-qPCR) assay for clinical Zika diagnosis.

OBJECTIVE: The nucleic acid-based polymerase chain reaction (PCR) assay is commonly applied to detect infection with Zika virus (ZIKV). However, the time- and labor-intensive sample pretreatment required to remove inhibitors that cause false-negative results in clinical samples is impractical for use in resource-limited areas. The aim was to develop a direct reverse-transcription quantitative PCR (dirRT-qPCR) assay for ZIKV diagnosis directly from clinical samples. METHODS: The combination of inhibitor-tolerant polymerases, polymerase enhancers, and dirRT-qPCR conditions was optimized for various clinical samples including blood and serum. Sensitivity was evaluated with standard DNA spiked in simulated samples. Specificity was evaluated using clinical specimens of other infections such as dengue virus and chikungunya virus. RESULTS: High specificity and sensitivity were achieved, and the limit of detection (LOD) of the assay was 9.5×101 ZIKV RNA copies/reaction. The on-site clinical diagnosis of ZIKV required a 5µl sample and the diagnosis could be completed within 2h. CONCLUSIONS: This robust dirRT-qPCR assay shows a high potential for point-of-care diagnosis, and the primer-probe combinations can also be extended for other viral detection. It realizes the goal of large-scale on-site screening for viral infections and could be used for early diagnosis and the prevention and control of viral outbreaks.

Bimetallic PdCu Nanocrystals Immobilized by Nitrogen-Containing Ordered Mesoporous Carbon for Electrocatalytic Denitrification.

Issues of uniform incorporation of catalytic functional species with controllable sizes, shapes, compositions, and functions into porous carbon scaffolds remain significant challenges toward enriching and boosting performance. Here, we develop a straightforward approach that introduces dicyandiamide as a nitrogen source to chelate with metal species and combines with the surfactant-templating self-assembly method for the fabrication of highly dispersed catalysts anchored in nitrogen-containing ordered mesoporous carbon (NOMC). As a result, these functional catalyst (such as PdCu nanocrystals)-embedded NOMC composites manifest a synergistic catalytic capability for the electroreduction of nitrate in neutral electrolyte, with more than 90% nitrate removed under an ultra-low concentration of 100 ppm and a high nitrogen selectivity of 60% after 10 repeated tests.

Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families.

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor.

Eukaryotic elongation factor-2 kinase (eEF2K) relays growth and stress signals to protein synthesis through phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2). 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) is a widely accepted inhibitor of mammalian eEF2K and an efficacious anti-proliferation agent against different cancer cells. It implied that eEF2K could be an efficacious anticancer target. However, eEF2K siRNA was ineffective against cancer cells including those sensitive to NH125. To test if pharmacological intervention differs from siRNA interference, we identified a highly selective small molecule eEF2K inhibitor A-484954. Like siRNA, A-484954 had little effect on cancer cell growth. We carefully examined the effect of NH125 and A-484954 on phosphorylation of eEF2, the known cellular substrate of eEF2K. Surprisingly, NH125 increased eEF2 phosphorylation, whereas A-484954 inhibited the phosphorylation as expected for an eEF2K inhibitor. Both A-484954 and eEF2K siRNA inhibited eEF2K and reduced eEF2 phosphorylation with little effect on cancer cell growth. These data demonstrated clearly that the anticancer activity of NH125 was more correlated with induction of eEF2 phosphorylation than inhibition of eEF2K. Actually, induction of eEF2 phosphorylation was reported to correlate with inhibition of cancer cell growth. We compared several known inducers of eEF2 phosphorylation including AMPK activators and an mTOR inhibitor. Interestingly, stronger induction of eEF2 phosphorylation correlated with more effective growth inhibition. We also explored signal transduction pathways leading to NH125-induced eEF2 phosphorylation. Preliminary data suggested that NH125-induced eEF2 phosphorylation was likely mediated through multiple pathways. These observations identified an opportunity for a new multipathway approach to anticancer therapies.

Investigation of novel 7,8-disubstituted-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones as potent Chk1 inhibitors.

The synthesis and structure-activity relationships (SAR) of Chk1 inhibitors based on a 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one core are described. Specifically, an exploration of the 7 and 8 positions on this previously disclosed core afforded compounds with improved enzymatic and cellular potency.

Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics.

A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome profiling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl)ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies.

Synthesis and in-vitro biological activity of macrocyclic urea Chk1 inhibitors.

A variety of macrocyclic urea compounds were prepared as potent Chk1 inhibitors by modifying the C5 position of the benzene ring of the macrocyclic urea with ether moieties, aliphatic carbon chains, amide and halides. Enzymatic activity less than 20nM was observed in 29 of 40 compounds. Compounds 14, 46d, and 48j provided the best overall results in the cellular assays as they abrogated doxorubicin-induced cell cycle arrest (IC(50)=3.31, 3.08, and 3.13microM) and enhanced doxorubicin cytotoxicity (IC(50)=0.54, 1.27, and 0.96microM) while displaying no single agent activity, respectively.

Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: improving oral biovailability.

A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.