Research on the Combustion Performance of Municipal Solid Waste in Different Sorting Scenarios: Thermokinetics Investigation via TG-DSC-FTIR-MS.

Waste sorting is regarded as one of the most important strategies for municipal solid waste (MSW) management. The changes in the combustion parameters after MSW sorting had a significant impact on the actual operation of the boiler. In the present study, the effects of heating rate on combustion characteristics and dynamics of MSW in different sorting scenarios were studied using the thermogravimetry (TG)-differential scanning calorimetry (DSC)-Fourier transform infrared (FTIR)-mass spectrometry (MS) technique. TG-DSC analysis showed that the heat released from MSW combustion at different heating rates ranged from 1394.1 to 4130.1 J/g. According to the TG-DTG curves, the combustibility of 30% sorted MSW was increased by 1.2 times compared to that of the unsorted scenario. In the 30% sorted scenario, the average activation energies were estimated to be 161.24 and 159.93 kJ/mol based on the Flynn-Wall-Ozawa (FWO) and Kissinger-Akahira-Sunose (KAS) methods, respectively. Based on the Coats-Redfern (CR) method, the minimum activation energies for unsorted and 20% sorted scenarios were 148.74 and 135.53 kJ/mol at 523 to 606 K, respectively, while they were 29.42 and 33.22 kJ/mol at 606 to 780 K. XRF analysis showed that the alkali and alkaline earth metal oxides in the ash contributed to a high risk of slagging and scaling. This work can provide a scientific basis for the real situation of MSW incineration.

CNTN1 Aggravates Neuroinflammation and Triggers Cognitive Deficits in Male Mice by Boosting Crosstalk between Microglia and Astrocytes.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors.

Histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1) are attractive targets for epigenetic cancer therapy. There is an intimate interplay between the two enzymes. HDACs inhibitors have shown synergistic anticancer effects in combination with LSD1 inhibitors in several types of cancer. Herein, we describe the discovery of compound 5e, a highly potent HDACs inhibitor (HDAC1/2/6/8; IC50 = 2.07/4.71/2.40/107 nM) with anti-LSD1 potency (IC50 = 1.34 µM). Compound 5e exhibited marked antiproliferative activity in several cancer cell lines. 5e effectively induced mitochondrial apoptosis with G2/M phase arrest, inhibiting cell migration and invasion in MGC-803 and HCT-116 cancer cells. It also showed good liver microsomal stability and acceptable pharmacokinetic parameters in SD rats. More importantly, orally administered compound 5e demonstrated higher in vivo antitumor efficacy than SAHA in the MGC-803 (TGI = 71.5%) and HCT-116 (TGI = 57.6%) xenograft tumor models accompanied by good tolerability. This study provides a novel lead compound with dual inhibitory activity against HDACs and LSD1 to further develop epigenetic drugs for solid tumor therapy. Further optimization is needed to improve the LSD1 activity to achieve dual inhibitors with balanced potency on LSD1 and HDACs.

Deaminative Cyclization of Tertiary Amines for the Synthesis of 2-Arylquinoline Derivatives with a Nonsubstituted Vinylene Fragment.

With triethylamine as a vinylene source, a convenient protocol for the regioselective synthesis of ß,γ-nonsubstituted 2-arylquinolines from aldehydes and arylamines has been accomplished. The deaminative cyclization is also extended to long-chain tertiary alkylamines, enabling diverse alkyl groups to be concurrently installed into the pyridine rings. This process demonstrates a new conversion pathway for the simultaneous dual C(sp3)-H bond functionalization of tertiary amines, wherein the transient acyclic enamines generated in situ undergo the Povarov reaction.

An oligosaccharide marker for rapid authentication of edible bird's nest.

Edible bird's nest (EBN) is a popular and expensive food material. The limited supply and great demand result in the use of adulterants. The authenticity concern is raised due to the lack of appropriate quality markers. Herein, this study aims to provide a specific oligosaccharide marker for rapid EBN authentication. Comparing the benzocaine (ABEE)-labeled saccharide profiles of multiple batches of EBN and adulterants indicates seven unique EBN oligosaccharides. The most abundant one, named BNM001, was selected as a marker and characterized to be Neu5Ac (2-3) Gal by MS and NMR spectra. This new oligosaccharide marker enables a rapid authentication of EBN within 10 min. ABEE labelling of this marker further upgraded the accuracy and sensitivity of the LC-qTOF-MS quantitative analysis. The relative marker content was associated with the quality of EBN products. These results suggest a specific and efficient quality marker for rapid authentication of EBN and related products.

Possibility for double optimization of siRNA intracellular delivery efficiency and antibacterial activity: Structure screening of pH-sensitive triblock amphiphilic polycation micelles.

Optimal combination of hydrophobic-hydrophilic balance, proton buffering and electrostatic interaction is the key issue for designing polycations as efficient gene vectors and antibacterial agents. Herein, we screened a series of pH-sensitive quaternary ammonium-based amphiphilic triblock copolymers, mPEG2k-P(DPAa/DMAb)-PQAc (TDDE-x), which had different pKa values and proton buffering capacities. Significantly, we found that both the highest siRNA intracellular delivery efficiency and the strongest antibacterial capacity occurred on TDDE-3 micelles with the segment structure of mPEG2k-P(DPA50/DMA56)-PQA55. The TDDE-3/siRNA complex achieved 67% silencing efficiency on H9C2 cells (N/P = 5, 50 nM siRNA), higher than the advanced commercial transfection reagents RNAiMAX (58%) and Lipo2000 (30%). Moreover, TDDE-3 micelles showed quite low MICs of 32 µg/mL and 8 µg/mL against E. coli and S. aureus, respectively. Further studies on the structure-function relationship indicated that TDDE-3 micelles could mediate robust endosome escape and siRNA cytosolic release, and strong bacterial cell membrane-destabilizing function. Undoubtedly, this work reveals the possibility for double optimization of siRNA intracellular delivery efficiency and antibacterial activity of amphiphilic polycations by reasonable structure design, which is significant for low-cost development and clinical translation of efficient multifunctional polycations.

Open-Air Dual-Diamination of Aromatic Aldehydes: Direct Synthesis of Azolo-Fused 1,3,5-Triazines Facilitated by Ammonium Iodide.

A new and practical protocol for the synthesis of medicinally privileged azolo[1,3,5]triazines by simply heating under air has been presented. The in situ generated N-azolo amidines from commercially available aromatic aldehydes and 3-aminoazoles with ammonium iodide undergo the second diamination to accomplish the [3 + 1 + 1 + 1] heteroannulation reaction. This convenient process is appreciated by high efficiency, broad substrate scope, gram-scale synthesis, and operational simplicity under reagent-free conditions.

A specific and bioactive polysaccharide marker for Cordyceps.

Cordyceps is one of the most expensive and widely used functional foods. But the authenticity is still a concern due to the lack of appropriate markers. By targeting polysaccharides, this study aimed to develop a specific, and bioactive marker for Cordyceps. Firstly, the results of screening tests of 250 samples by examining both genetic markers and polysaccharide profile showed that a unique polysaccharide fraction (named CCP) was particular to the caterpillar parts. Its potential as a marker was further demonstrated by its ability to induce NO and cytokine production in RAW 264.7 cells. CCP was characterized to be an α-1,4-glucan with a branch at C-6 by the conventional structure analyzing and de novo oligosaccharides sequencing. The content of CCP was closely correlated to the traditional classification criteria. Generally, CCP was a marker that simultaneously enables qualitative and quantitative analysis of Cordyceps.

Harnessing pH-Sensitive Polycation Vehicles for the Efficient siRNA Delivery.

pH-sensitive hydrophobic segments have been certificated to facilitate siRNA delivery efficiency of amphiphilic polycation vehicles. However, optimal design concepts for these vehicles remain unclear. Herein, by studying the library of amphiphilic polycations mPEG-PAMA50-P(DEAx-r-D5Ay) (EAE5x/y), we concluded a multifactor matching concept (pKa values, "proton buffering capacities" (BCs), and critical micelle concentrations (CMCs)) for polycation vehicles to improve siRNA delivery efficiency in vitro and in vivo. We identified that the stronger BCs in a pH 5.5-7.4 subset induced by EAE548/29 (pKa = 6.79) and EAE539/37 (pKa = 6.20) are effective for siRNA delivery in vitro. Further, the stronger BCs occurred in a narrow subset of pH 5.5-6.5 and the lower CMC attributed to higher siRNA delivery capacity of EAE539/37 in vivo than EAE548/29 after intravenous administration and subcutaneous injection. More importantly, 87.2% gene knockdown efficacy was achieved by EAE539/37 via subcutaneous injection, which might be useful for an mRNA vaccine adjuvant. Furthermore, EAE539/37 also successfully delivered siRRM2 to tumor via intravenous administration and received highly efficient antitumor activity. Taken together, the suitable pKa values, strong BCs occurred in pH 5.5-6.5, and low CMCs were probably the potential solution for designing efficient polycationic vehicles for siRNA delivery.

A Atractylodes lancea polysaccharide inhibits metastasis of human osteosarcoma U-2 OS cells by blocking sialyl Lewis X (sLex )/E-selectin binding.

In this study, a new water and alkaline-soluble polysaccharide (ALP), with an average molecular weight of 6.63 × 104  Da, was successfully purified from the rhizomes of Atractylodes lancea. GC analysis demonstrated that ALP was a kind of glucan. The effect of the ALP on the interaction between E-selectin and sialyl Lewis X (sLex ) was examined in human osteosarcoma U-2 OS cells. It was obvious that the expression of sLex antigen on the surface of U-2 OS cells was visible under fluorescence microscopy. The addition of ALP (0.5, 1 and 2 mg/mL) resulted in a marked inhibition on the adhesion, migration and invasion of U-2 OS cells to human umbilical vein endothelial cells (HUVECs), which was achieved by the decreased sLex expression on U-2 OS cells. Additionally, the induction of apoptosis can be observed in U-2 OS cells following ALP treatment using TUNEL staining and Annexin V-FITC/PI double-staining analysis on flow cytometry. In conclusion, these results indicated that ALP exerted anti-metastatic activity towards osteosarcoma cells via inhibition of sLex /E-selectin binding, which suggested that ALP could be a potent agent for human osteosarcoma intervention.

Lipid/Hyaluronic Acid-Coated Doxorubicin-Fe3O4 as a Dual-Targeting Nanoparticle for Enhanced Cancer Therapy.

Development of a delivery system to lower systemic toxicity and enhance doxorubicin (DOX) antitumor efficacy against multi-drug resistant (MDR) tumors is of great clinical significance. Here, lipid/hyaluronic acid (HA)-coated DOX-Fe3O4 was characterized to determine its optimal safety and efficacy on a tumor. DOX was first conjugated onto the Fe3O4 NPs surface, which was subsequently coated with phosphatidylcholine (PC) lipids, which consisted of a tumor cell-targeting HA ligand, to generate a dual-targeting nanoparticle (NP). DOX-Fe3O4 synthesis was validated by the Fourier-transform infrared (FT-IR) analysis results. Core-shell PC/HA@DOX-Fe3O4 formation, which had an average particle size of 48.2 nm, was observed based on the transmission electron microscopy (TEM) and dynamic laser light scattering (DLS) results. The saturation magnetization value of PC/HA@DOX-Fe3O4 was discovered to be 28 emu/g using vibrating-sample magnetometry. Furthermore, the designed PC/HA@DOX-Fe3O4 achieved greater MCF-7/ADR cellular uptake and cytotoxicity as compared with DOX. In addition, PC/HA@DOX-Fe3O4 exhibited significant DOX tumor-targeting capabilities and enhanced tumor growth inhibition activity in the xenograft MCF-7/ADR tumor-bearing nude mice following magnetic attraction and ligand-mediated targeting, with less cardiotoxicity. Therefore, PC/HA@DOX-Fe3O4 is a potential candidate for MDR tumor chemotherapy. Graphical abstract.

I2-Catalyzed Aerobic α,ß-Dehydrogenation and Deamination of Tertiary Alkylamines: Highly Selective Synthesis of Polysubstituted Pyrimidines via Hidden Acyclic Enamines.

A novel and efficient entrance to the pyrimidine skeleton has been presented via the α,ß-dehydrogenation and deamination of tertiary alkylamines. This I2-catalyzed dehydrogenative multicomponent procedure utilizes simple aldehydes to trap the hidden enamine intermediates and suspend generation of azadienes from amidines, enabling the difunctionalization of a vicinal C(sp3)-H bond. These studies provide valuable possibilities for the introduction of aliphatic substituents and show how to switch to a new reactive modality.

Amide derivatives of Gallic acid: Design, synthesis and evaluation of inhibitory activities against in vitro α-synuclein aggregation.

Gallic acid (GA), a natural phenolic acid, has received numerous attention because of its anti-oxidative, anti-inflammatory, and anti-cancer activity. More importantly, GA can act as an efficient inhibitor of α-Synuclein (α-Syn) aggregation at early stages. Nevertheless, some evidences suggest that GA is unlikely to cross the blood-brain barrier because of its high hydrophilicity. Hence, GA may not be considered as a promising candidate or entering brain and directly affecting the central nervous system. Accordingly, we have designed and synthesized a series of amide derivatives of GA, some of which possess appropriate lipophilicity and hydrophilicity with LogP (2.09-2.79). Meanwhile, these sheet-like conjugated compounds have good π-electron delocalization and high ability of hydrogen-bond formation. Some compounds have shown better in vitro anti-aggregation activities than GA towards α-Syn, with IC50 down to 0.98 µM. The valid modification strategy of GA is considered an efficient way to discover novel inhibitors of α-Syn aggregation.

An oligosaccharide-marker approach to quantify specific polysaccharides in herbal formula by LC-qTOF-MS: Danggui Buxue Tang, a case study.

Polysaccharides have broad bioactivities and are major components of water decoction of herb formulae. However, the quality control of polysaccharides remains a challenge. Oligosaccharide-fragment approach has been considered in elucidating chemical structures of polysaccharides, but never been used for quantitation. Using reference chemicals and a real sample Danggui Buxue Tang (DBT) in this study, an oligosaccharide-marker approach was established to quantify specific polysaccharides. Firstly, linear relationships between parent polysaccharides and hydrolysis-produced daughter oligosaccharides were verified using reference polysaccharides. Then in case of DBT, two fluorescence-labeled oligosaccharides with high specificity to individual parent polysaccharides were selected as markers. They were easily isolated and identified. Their potential in quantification of parent polysaccharides were satisfactorily validated in terms of linearity (r≥0.99), repeatability (RSD ≤ 8.4 %), and spike recovery (≥80 %). This method could be a promising approach for quality assessment of polysaccharides in herbal formulae.

Fluorometric determination of ssDNA based on functionalized magnetic microparticles and DNA supersandwich self-assemblies.

A method is described for the determination of DNA via nucleic acid amplification by using nucleic acid concatemers that result from DNA supersandwich self-assemblies (SSAs). The method employs two auxiliary probes to form self-assembled biotin SSAs. These exhibit strong fluorescence if labeled with intercalator SYBR Green I. In the presence of the target (as exemplified for a 30-mer), streptavidin is released from the surface of the functionalized magnetic microparticles (FMMPs) by competitive hybridization on the surface. However, the SSA products do not conjugate to the FMMPs. This leads to a large amount of SYBR Green I intercalated into the concatemers and eventually results in amplified fluorescence in the supernate. The SSA products can be prepared beforehand, and amplification therefore can be completed within 50 min. The method is more efficient than any other conventional amplification. The detection limit for the 30-mer is 26.4 fM which is better by a factor of 10 compared to other amplification methods. Conceivably, the method can be further extended to the determination of a wide variety of targets simply by replacing the sequences of the probes. Finally, this rapid and highly sensitive method was employed for detection of Ebola virus gene (≈30-mer) and ATP in spiked serum with satisfactory results. Graphical abstract A high sensitivity and efficiency bioassay is described based on functionalized magnetic microparticles and DNA supersandwich self-assemblies.

Rational Design of Nanoparticles to Overcome Poor Tumor Penetration and Hypoxia-Induced Chemotherapy Resistance: Combination of Optimizing Size and Self-Inducing High Level of Reactive Oxygen Species.

One tough question induced by the hypoxia in cancer tissue is resistance to anticancer drugs basing on the reactive oxygen species (ROS) mechanism. Furthermore, the hypoxic regions locate in the center of tumor where tumor cells are easily residual and survival due to the poor drug-delivery efficiency even with nanocarriers. In this paper, these problems were well addressed through the rational combination of the enhanced penetration, self-inducing high level of intracellular ROS, and synchronously pH-sensitive drug release, realized by a simple structural and accessible copolymer, poly(poly(ethylene glycol) methyl ether methacrylate-co-(2-methylpropenoic acid-glycerol-cinnamaldehyde)) (PgEMC). For one thing, PgEMC could self-assemble into stable nanoparticles with PEG shell and optimizing diameters of 60 nm to simultaneously facilitate long blood circulation and deep tumor penetration. Second, cinnamylaldehyde moieties could detach from PgEMC NPs in intracellular acidic environment and trigger high level of ROS to allay the doxorubicin (DOX) resistance induced by hypoxia in solid malignancies. Furthermore, the DOX payload in PgEMC NPs could be synchronously released with the intracellular disassembly of PgEMC NPs due to the detaching of cinnamylaldehyde moieties. In 4T1 cells treated with PgEMC/DOX NPs, remarkable elevation of ROS level and enhanced DOX sensitivity in hypoxia environment were observed in in vitro studies. The results of tumor spheroid penetration indicated that 60 nm sized DOX-loaded PgEMC NPs (PgEMC60/DOX) could distribute into deep site of tumor at a high intensity. In vivo studies using a 4T1 breast tumor model, PgEMC60/DOX NPs, showed significant inhibition over 95.4% of the tumor growth. These results reveal that integrating optimizing size, self-inducing ROS, and pH-sensitive drug release into one small-sized nanoparticle can efficiently overcome the poor tumor penetration and hypoxia-induced chemotherapy resistance.

Aerobic α,ß-C(sp3)-H Bond Difunctionalization and C-N Bond Cleavage of Triethylamine: Difunctional Ammonium Iodide Enabling the Regioselective Synthesis of 4-Arylpyrimido[1,2-b]indazoles.

A novel method for the regioselective synthesis of 4-arylpyrimido[1,2-b]indazoles has been developed via the dual C(sp3)-H bond functionalization and C-N bond cleavage of triethylamine. The elusive acyclic enamine intermediates are effectively in situ generated and captured by aromatic aldehydes to form a wide array of tricyclic products from 3-aminoindazoles under the NH4I-mediated aerobic oxidative conditions. This reaction features easily available feedstock, green and economic conditions, and valuable products.

Oligosaccharide-marker approach for qualitative and quantitative analysis of specific polysaccharide in herb formula by ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry: Dendrobium officinale, a case study.

Qualitative and quantitative analysis of polysaccharides in herb formula remain challenge due to the limited choices of analytical methods concerning the intrinsic characteristics of large molecular mass. Herein, an oligosaccharide-marker approach was newly developed for quality assessment of polysaccharides in herbal materials, using Dendrobium officinale as a case study. This method involved partial acid hydrolysis of D. officinale polysaccharide (DOP) followed by p-aminobenzoic ethyl ester (ABEE) derivatization. Two ABEE-labeled oligosaccharides namely, Te-Man-ABEE and Pen-Man-ABEE, were selected as chemical markers due to their high specificity in herb formula. The linear relationship between the content of these two markers and the content of DOP was then successfully established respectively. The linear relationship was further transformed to that between peak area of chemical markers and DOP content so that chemical markers were not necessary to be isolated for analysis. This linear relationship was systemically validated in terms of precision and accuracy. The results showed that these two oligosaccharide-markers presented a good linear relationship with DOP (R2 ≥ 0.997) in the range of 0.68-16.02 µg. These markers also demonstrated satisfactory precision (RSD < 7.0%), and recovery (91.41%-118.30%) in real sample determination. Additionally, there was no significant difference between the results given by the two chemical markers as the RSD values were not more than 7.0%. While concerning the results given by the oligosaccharide-markers and the previously-published polysaccharide marker, the RSD value was not more than 6.4%. These suggest that the oligosaccharide-marker approach is a simple, quick, and reliable method to qualitatively and quantitatively determine of specific polysaccharide in herb formula.

Anti-oligomerization sheet molecules: Design, synthesis and evaluation of inhibitory activities against α-synuclein aggregation.

Aggregation of α-synuclein (α-Syn) play a key role in the development of Parkinson Disease (PD). One of the effective approaches is to stabilize the native, monomeric protein with suitable molecule ligands. We have designed and synthesized a series of sheet-like conjugated compounds which possess different skeletons and various heteroatoms in the two blocks located at both ends of linker, which have good π-electron delocalization and high ability of hydrogen-bond formation. They have shown anti-aggregation activities in vitro towards α-Syn with IC50 down to 1.09 µM. The molecule is found binding in parallel to the NACore within NAC domain of α-Syn, interfering aggregation of NAC region within different α-Syn monomer, and further inhibiting or slowing down the formation of α-Syn oligomer nuclei at lag phase. The potential inhibitor obtained by our strategy is considered to be highly efficient to inhibit α-Syn aggregation.

Comprehensive comparison of polysaccharides from Ganoderma lucidum and G. sinense: chemical, antitumor, immunomodulating and gut-microbiota modulatory properties.

Both Ganoderma lucidum (GL) and G. sinense (GS) are used as Lingzhi in China. Their functions are assumed to mainly derive from triterpenes and polysaccharides; however, the two species have very different triterpenes profiles, if this was the case, then the bioactivity of these two species should differ. Instead, could the polysaccharides be similar, contributing to the shared therapeutic basis? In this study, two main polysaccharide fractions from different batches of GL and GS were systematically compared by a series of chemical and biological experiments. The results showed that the polysaccharides from two species shared the same structural features in terms of mono-/oligo-saccharide profiles, molecular size, sugar linkages, and IR/NMR spectra. In addition, these polysaccharides showed similar tumor-suppressive activity in mice. Further study on RAW264.7 cells indicated that these polysaccharides exhibited similar inducing effects to macrophages, as evaluated in the phagocytosis function, NO/cytokines production, inhibition against the viability and migration of cancer cells. Mechanistic investigation revealed the identical activation via TLR-4 related MAPK/NF-κB signaling pathway and gut-microbiota modulatory effects. In summary, GL and GS polysaccharides presented similar chemical features, antitumor/immunomodulating activities and mechanism; this establishes polysaccharides as the active principles and supports the official use of both species as Lingzhi.