Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Risk assessment of imported malaria in China: a machine learning perspective.

BACKGROUND: Following China's official designation as malaria-free country by WHO, the imported malaria has emerged as a significant determinant impacting the malaria reestablishment within China. The objective of this study is to explore the application prospects of machine learning algorithms in imported malaria risk assessment of China. METHODS: The data of imported malaria cases in China from 2011 to 2019 was provided by China CDC; historical epidemic data of malaria endemic country was obtained from World Malaria Report, and the other data used in this study are open access data. All the data processing and model construction based on R, and map visualization used ArcGIS software. RESULTS: A total of 27,088 malaria cases imported into China from 85 countries between 2011 and 2019. After data preprocessing and classification, clean dataset has 765 rows (85 * 9) and 11 cols. Six machine learning models was constructed based on the training set, and Random Forest model demonstrated the best performance in model evaluation. According to RF, the highest feature importance were the number of malaria deaths and Indigenous malaria cases. The RF model demonstrated high accuracy in forecasting risk for the year 2019, achieving commendable accuracy rate of 95.3%. This result aligns well with the observed outcomes, indicating the model's reliability in predicting risk levels. CONCLUSIONS: Machine learning algorithms have reliable application prospects in risk assessment of imported malaria in China. This study provides a new methodological reference for the risk assessment and control strategies adjusting of imported malaria in China.

P(NMe2)3-Mediated Regioselective N-Alkylation of 2-Pyridones via Direct Deoxygenation of α-Keto Esters.

A practical and regioselective direct N-alkylation of 2-pyridones is enabled by use of α-keto esters in the P(NMe2)3-mediated deoxygenation process. The reaction proceeds under mild conditions to produce N-alkylated 2-pyridones with high selectivity and generality, and the protocol is shown to be applicable for the scale-up synthesis, which makes it promising for practical applications.

Precision Synthesis of Polysarcosine via Controlled Ring-Opening Polymerization of N-Carboxyanhydride: Fast Kinetics, Ultrahigh Molecular Weight, and Mechanistic Insights.

The rapid and controlled synthesis of high-molecular-weight (HMW) polysarcosine (pSar), a potential polyethylene glycol (PEG) alternative, via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is rare and challenging. Here, we report the well-controlled ROP of sarcosine NCA (Sar-NCA) that is catalyzed by various carboxylic acids, which accelerate the polymerization rate up to 50 times, and enables the robust synthesis of pSar with an unprecedented ultrahigh molecular weight (UHMW) up to 586 kDa (DP ∼ 8200) and exceptionally narrow dispersity (D̵) below 1.05. Mechanistic experiments and density functional theory calculations together elucidate the role of carboxylic acid as a bifunctional catalyst that significantly facilitates proton transfer processes and avoids charge separation and suggest the ring opening of NCA, rather than decarboxylation, as the rate-determining step. UHMW pSar demonstrates improved thermal and mechanical properties over the low-molecular-weight counterparts. This work provides a simple yet highly efficient approach to UHMW pSar and generates a new fundamental understanding useful not only for the ROP of Sar-NCA but also for other NCAs.

Emerging Xene-Based Single-Atom Catalysts: Theory, Synthesis, and Catalytic Applications.

In recent years, the emergence of novel 2D monoelemental materials (Xenes), e.g., graphdiyne, borophene, phosphorene, antimonene, bismuthene, and stanene, has exhibited unprecedented potentials for their versatile applications as well as addressing new discoveries in fundamental science. Owing to their unique physicochemical, optical, and electronic properties, emerging Xenes have been regarded as promising candidates in the community of single-atom catalysts (SACs) as single-atom active sites or support matrixes for significant improvement in intrinsic activity and selectivity. In order to comprehensively understand the relationships between the structure and property of Xene-based SACs, this review represents a comprehensive summary from theoretical predictions to experimental investigations. Firstly, theoretical calculations regarding both the anchoring of Xene-based single-atom active sites on versatile support matrixes and doping/substituting heteroatoms at Xene-based support matrixes are briefly summarized. Secondly, controlled synthesis and precise characterization are presented for Xene-based SACs. Finally, current challenges and future opportunities for the development of Xene-based SACs are highlighted.

Base Metal-Controlled Chemodivergent Cyclization of Propargylamines for the Atom-Economic Synthesis of Nitrogen Heterocycles.

Herein, a base metal-enabled chemodivergent cyclization of propargylamines for the atom-economic construction of nitrogen heterocycles has been developed. Due to the different modes of activation of metal to propargylamine, copper-catalyzed 6-endo-dig cyclization generates functionalized 2-substitued quinoline-4-carboxylates, while iron-promoted cascade amino Claisen rearrangement, aromatization, and aza-Michael addition afford diverse 2-substituted indole-3-carboxylate derivatives. Excellent selectivity, broad functional group tolerance, mild conditions, and flexible late-stage functionalization illustrate the high efficiency and synthetic utility of this chemodivergent reaction.

Exploring a Linear Combination Feature for Predicting the Conductance of Parallel Molecular Circuits.

An accurate rule for predicting conductance is the cornerstone of developing molecular circuits and provides a promising solution for miniaturizing electric circuits. The successful prediction of series molecular circuits has proven the possibility of establishing a rule for molecular circuits under quantum mechanics. However, the quantitatively accurate prediction has not been validated by experiments for parallel molecular circuits. Here we used 1,3-dihydrobenzothiophene (DBT) to build the parallel molecular circuits. The theoretical simulation and single-molecule conductance measurements demonstrated that the conductance of the molecule containing one DBT is the unprecedented linear combination of the conductance of the two individual channels with respective contribution weights of 0.37 and 0.63. With these weights, the conductance of the molecule containing two DBTs is predicted as 1.81 nS, matching perfectly with the measured conductance (1.82 nS). This feature offers a potential rule for quantitatively predicting the conductance of parallel molecular circuits.

Sequential In Situ-Formed Kukhtin-Ramirez Adduct and P(NMe2)3-Catalyzed O-Phosphination of α-Dicarbonyls with P(O)-H.

O-Phosphination of α-dicarbonyls via sequential in situ formation of a Kukhtin-Ramirez adduct and a P(NMe2)3-catalyzed process has been exploited for the synthesis of α-phosphoryloxy carbonyls. A range of P(O)-H derivatives, including diarylphosphine oxides, arylphosphinates, and phosphinates, are competent candidates to be introduced into the α-dicarbonyls in this transformation, and various α-phosphoryloxy carbonyls are obtained. This approach possesses advantages of mild conditions, simple operations, atom economy, high efficiency, and gram-scale synthesis, which make it promising in the synthesis toolbox.

Construction of Reinforced Self-Cleaning and Efficient Photothermal PDMS@GDY@Cu Sponges toward Anticorrosion and Antibacterial Applications.

Copper (Cu)-based materials are widely used in many fields from industry to life, including marine, medical apparatus and instruments, and microelectronic devices owing to their superior thermal, electrical, and mechanical properties. However, the interaction of copper with aggressive and fouling liquids under normal circumstances easily brings about severe bacterial accumulation, resulting in undesirable functionality degeneration and bacterial infections. In this contribution, we reported a novel copper-based sponge, polydimethylsiloxane (PDMS)@graphdiyne (GDY)@Cu, constructed by in situ synthesis of GDY on a commercial Cu sponge, followed by the modification of PDMS. The as-fabricated PDMS@GDY@Cu sponge not only possesses excellent self-cleaning activity against the pollution of daily drinks and dirt due to an improved static contact angle (~136°), but also display a remarkably enhanced anticorrosion performance, attributed to intimate coverage of chemically stable GDY and PDMS on the Cu sponge. Based on high photothermal effect of GDY, the PDMS@GDY@Cu sponge also displays significantly improved antibacterial activities under irradiation. In addition, due to excellent chemical stability of PDMS and GDY, self-cleaning behavior and photothermal-assisted antibacterial performance are well maintained after long-term attack of bacteria. These results demonstrate that GDY-based functional coatings hold great promises in the protection of copper devices under harsh conditions.

Rh-Catalyzed [4 + 1] Reaction of Cyclopropyl-Capped Dienes (but not Common Dienes) and Carbon Monoxide: Reaction Development and Mechanistic Study.

Transition-metal-catalyzed [4 + 1] reaction of dienes and carbon monoxide (CO) is the most straightforward and easily envisioned cyclization for the synthesis of five-membered carbocycles, which are ubiquitously found in natural products and functional molecules. Unfortunately, no test of this reaction was reported, and consequently, chemists do not know whether such kind of reaction works or not. Herein, we report that the [4 + 1] reaction of common dienes and CO cannot work, at least under the catalysis of [Rh(cod)Cl]2. However, using cyclopropyl-capped dienes (also named allylidenecyclopropanes) as substrates, the corresponding [4 + 1] reaction with CO proceeds smoothly in the presence of [Rh(cod)Cl]2. This [4 + 1] reaction, with a broad scope, provides efficient access to five-membered carbocyclic compounds of spiro[2.4]hept-6-en-4-ones. The [4 + 1] cycloadducts can be further transformed into other molecules by using the unique chemistry of cyclopropyl groups present in these molecules. The mechanism of this [4 + 1] reaction has been investigated by quantum chemical calculations, uncovering that cyclopropyl-capped dienes are strained dienes and the oxidative cyclization step in the [4 + 1] catalytic cycle can release this (angular) strain both kinetically and thermodynamically. The strain release in this step then propagates to all followed CO coordination/CO insertion/reductive elimination steps in the [4 + 1] catalytic cycle, helping the realization of this cycloaddition reaction. In contrast, common dienes (including cyclobutyl-capped dienes) do not have such advantages and their [4 + 1] reaction suffers from energy penalty in all steps involved in the [4 + 1] catalytic cycle. The reactivity of ene-allenes for the [4 + 1] reaction with CO is also discussed.

TAK-242 protects against oxygen-glucose deprivation and reoxygenation-induced injury in brain microvascular endothelial cells and alters the expression pattern of lncRNAs.

Background: Deep hypothermic circulatory arrest (DHCA) is a technique used during the surgical treatment of aneurysms of the thoracic aorta in adult patients, and complex congenital heart disease in neonates. And brain microvascular endothelial cells (BMECs) are essential components of the cerebrovascular network and participate in maintaining the blood-brain barrier (BBB) and brain function. In our previous study, we found that oxygen-glucose deprivation and reoxygenation (OGD/R) activated Toll-like receptor 4 (TLR4) signaling in BMECs, and induced pyroptosis and inflammation. In this study, we further investigated the potential mechanism of ethyl(6R)-6-[N-(2-Chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate (TAK-242) on BMECs under OGD/R, as in patients with sepsis, the TAK-242 was tested in clinical trials. Methods: To confirm the function of TAK-242 on BMECs under OGD/R, cell viability, inflammatory factors, inflammation-associated pyroptosis, and nuclear factor-κB (NF-κB) signaling were determined using Cell Counting Kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA), and western blotting, respectively. To investigate the lncRNAs associated with TLR4 during OGD/R, long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression patterns were profiled with RNA deep sequencing. Moreover, to confirm whether lncRNA-encoded short peptides, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used. Results: Relative control group, OGD/R inhibited the cell viability, increased the section of inflammatory factors secretion, including IL-1ß, IL-6, and TNF-α, and promoted the pathways of TLR4/NLRP3/Caspase-1 and TLR4/NF-κB. However, TAK-242 + OGD/R group promoted OGD/R cell viability, decreased OGD/R-induced inflammatory factors secretion, and inhibited the pathways of TLR4/NLRP3/Caspase-1 and TLR4/NF-κB. In addition, AABR07000411.1, AABR070006957.1, and AABR070008256.1 were decreased in OGD/R cells compared with controls, but TAK-242 restored their expression under OGD/R condition. AABR07000473.1, AC130862.4, and LOC10254972.6 were induced by OGD/R, but were suppressed in TAK-242 + OGD/R cells compared with OGD/R. Moreover, AABR07049961.1, AC127076.2, AABR07066020.1, and AABR07025303.1-encoded short peptides were dysregulated in OGD/R cells, and TAK-242 attenuated the dysregulation of AABR07049961.1, AC127076.2, and AABR07066020.1-encoded short peptides. Conclusions: TAK-242 alters the expression pattern of lncRNAs in OGD/R cells, and differently expressed lncRNAs may exert a protective effect against OGD/R injury through a mechanism of competing endogenous RNA (ceRNA) and encoding short peptides. These findings maybe provide a new theory basis for the treatment of DHCA.

Electro-catalytic Iodoplumbate Incorporating Two Types of Polymeric Anions.

The development of the most promising electro-catalysts for the high-performance hydrogen evolution reaction (HER) in neutral media is exceedingly desirable. Here, the convenient hydrothermal reaction of PbI2, 3-pyrazinyl-1,2,4-triazole (3-pt), KI, and methanol in HI aqueous solution acquired an organic hybrid iodoplumbate [mtp][Pb2I5][PbI3]·0.5H2O (denoted as PbI-1, mtp2+ = 3-(1,4-dimethyl-1H-1,2,4-triazol-4-ium-3-yl)-1-methylpyrazin-1-ium), which not only provided an infrequent in situ organic mtp2+ cation that originated from the hydrothermal N-methylation reaction of 3-pt in acidic KI solution but also offered the rare example of organic hybrid iodoplumbate incorporating both one-dimensional (1-D) [PbI3-]n and two-dimensional (2-D) [Pb2I5-]n polymeric anions with one configuration of the mtp2+ cation. PbI-1 was applied for the construction of a Ni nanoparticle decorating the PbI-1 electrode (Ni/PbI-1/NF) via successive coating and electrodeposition onto the porous Ni foam (NF) support. The fabricated Ni/PbI-1/NF electrode that served as the cathodic catalyst showed excellent HER electro-catalytic activity.

Chemical characteristics and spatiotemporal variation of marine fine particles for clustered channels of air masses transporting toward remote background sites in East Asia.

This study investigated the chemical characteristics, spatiotemporal distribution, and source apportionment of marine fine particles (PM2.5) for clustered transport channels/routes of air masses moving toward three remote sites in East Asia. Six transport routes in three channels were clustered based on backward trajectory simulation (BTS) in the order of: West Channel > East Channel > South Channel. Air masses transported toward Dongsha Island (DS) came mainly from the West Channel, while those transported toward Green Island (GR) and Kenting Peninsula (KT) came mostly from the East Channel. High PM2.5 commonly occurred from late fall to early spring during the periods of Asian Northeastern Monsoons (ANMs). Marine PM2.5 was dominated by water-soluble ions (WSIs) which were predominated by secondary inorganic aerosols (SIAs). Although the metallic content of PM2.5 was predominated by crustal elements (Ca, K, Mg, Fe, and Al), enrichment factor clearly showed that trace metals (Ti, Cr, Mn, Ni, Cu, and Zn) came mainly from anthropogenic sources. Organic carbon (OC) was superior to elemental carbon (EC), while OC/EC and SOC/OC ratios in winter and spring were higher than those in other two seasons. Similar trends were observed for levoglucosan and organic acids. The mass ratio of malonic acid and succinic acid (M/S) was commonly higher than unity, showing the influences of biomass burning (BB) and secondary organic aerosols (SOAs) on marine PM2.5. We resolved that the main sources of PM2.5 were sea salts, fugitive dust, boiler combustion, and SIAs. Boiler combustion and fishing boat emissions at the site DS had higher contribution than those at the sites GR and KT. The highest/lowest contribution ratios of cross-boundary transport (CBT) were 84.9/29.6% in winter and summer, respectively.

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silyl Enol Ethers with Allylic Fluorides.

Lewis base catalyzed allylations of C-centered nucleophiles have been largely limited to the niche substrates with acidic C-H substituted for C-F bonds at the stabilized carbanionic carbon. Herein we report that the concept of latent pronucleophiles serves to overcome these limitations and allow for a variety of common stabilized C-nucleophiles, when they are introduced as the corresponding silylated compounds, to undergo enantioselective allylations using allylic fluorides. The reactions of silyl enol ethers afford the allylation products in good yields and with high degree of regio/stereoselectivity as well as diastereoselectivity when cyclic silyl enol ethers are used. Further examples of silylated stabilized carbon nucleophiles that undergo efficient allylation speak in favor of the general applicability of this concept to C-centered nucleophiles.

Recent Progress in Interface Engineering of Nanostructures for Photoelectrochemical Energy Harvesting Applications.

With rapid and continuous consumption of nonrenewable energy, solar energy can be utilized to meet the energy requirement and mitigate environmental issues in the future. To attain a sustainable society with an energy mix predominately dependent on solar energy, photoelectrochemical (PEC) device, in which semiconductor nanostructure-based photocatalysts play important roles, is considered to be one of the most promising candidates to realize the sufficient utilization of solar energy in a low-cost, green, and environmentally friendly manner. Interface engineering of semiconductor nanostructures has been qualified in the efficient improvement of PEC performances including three basic steps, i.e., light absorption, charge transfer/separation, and surface catalytic reaction. In this review, recently developed interface engineering of semiconductor nanostructures for direct and high-efficiency conversion of sunlight into available forms (e.g., chemical fuels and electric power) are summarized in terms of their atomic constitution and morphology, electronic structure and promising potential for PEC applications. Extensive efforts toward the development of high-performance PEC applications (e.g., PEC water splitting, PEC photodetection, PEC catalysis, PEC degradation and PEC biosensors) are also presented and appraised. Last but not least, a brief summary and personal insights on the challenges and future directions in the community of next-generation PEC devices are also provided.

Interfacial Engineering of Ni/V2 O3 Heterostructure Catalyst for Boosting Hydrogen Oxidation Reaction in Alkaline Electrolytes.

Alkaline fuel cells can permit the adoption of platinum group metal-free (PGM-free) catalysts and cheap bipolar plates, thus further lowering the cost. With the exploration of PGM-free hydrogen oxidation reaction (HOR) catalysts, nickel-based compounds have been considered as the most promising HOR catalysts in alkali. Here we report an interfacial engineering through the formation of nickel-vanadium oxide (Ni/V2 O3 ) heterostructures to activate Ni for efficient HOR catalysis in alkali. The strong electron transfer from Ni to V2 O3 could modulate the electronic structure of Ni sites. The optimal Ni/V2 O3 catalyst exhibits a high intrinsic activity of 0.038 mA cm-2 and outstanding stability. Experimental and theoretical studies reveal that Ni/V2 O3 interface as the active sites can enable to optimize the hydrogen and hydroxyl bindings, as well as protect metallic Ni from extensive oxidation, thus achieving the notable activity and durability.

Insights into the Antibacterial Properties of Complement Peptides C3a, C4a, and C5a across Vertebrates.

Complement peptides C3a, C4a, and C5a are important components of innate immunity in vertebrates. Although they diverged from a common ancestor, only C3a and C4a can act as antibacterial peptides in Homo sapiens, suggesting that C5a has evolved into a purely chemotactic molecule; however, the antibacterial properties of C3a, C4a, and C5a across vertebrates still require elucidation. In this article, we show that, unlike those in H. sapiens, Mus musculus C3a, C4a, and C5a all possess antibacterial activities, implying that the antibacterial properties of C3a, C4a, and C5a have evolved divergently in vertebrates. The extremely different net charge, a key factor determining the antibacterial activities of cationic antimicrobial peptides, of vertebrate C3a, C4a, and C5a supports this speculation. Moreover, the antibacterial activity of overlapping peptides covering vertebrate C3a, C4a, and C5a further strongly supports the speculation, because their activity is positively correlated with the net charge of source molecules. Notably, the structures of C3a, C4a, and C5a are conserved in vertebrates, and the inactive overlapping peptides can become antibacterial peptides if mutated to possess enough net positive charges, indicating that net charge is the only factor determining the antibacterial properties of vertebrate C3a, C4a, and C5a. More importantly, many vertebrate C3a-, C4a-, and C5a-derived peptides possess high antibacterial activities yet exhibit no hemolytic activities, suggesting the application potential in anti-infective therapy. Taken together, our findings reveal that vertebrate C3a, C4a, and C5a are all sources of antibacterial peptides that will facilitate the design of excellent peptide antibiotics.

Bismuth Quantum Dot (Bi QD)/Polydimethylsiloxane (PDMS) Nanocomposites with Self-Cleaning and Antibacterial Activity for Dental Applications.

In the oral microenvironment, bacteria colonies are easily aggregated on the tooth-restoration surface, in the manner of a biofilm, which usually consists of heterogeneous structures containing clusters of a variety of bacteria embedded in an extracellular matrix, leading to serious recurrent caries. In this contribution, zero-dimensional (0D) bismuth (Bi) quantum dots (QDs) synthesized by a facile solvothermal method were directly employed to fabricate a Bi QD/polydimethylsiloxane (PDMS)-modified tooth by simple curing treatment. The result demonstrates that the as-fabricated Bi QD/PDMS-modified tooth at 37 °C for 120 min not only showed significantly improved hydrophobic performance with a water contact angle of 103° and 115° on the tooth root and tooth crown, respectively, compared to that (~20° on the tooth root, and ~5° on the tooth crown) of the pristine tooth, but also exhibited excellent antibacterial activity against S. mutans, superior biocompatibility, and biosafety. In addition, due to the highly photothermal effect of Bi QDs, the antibacterial activity of the as-fabricated Bi QD/PDMS-modified tooth could be further enhanced under illumination, even at a very low power density (12 mW cm-2). Due to the facile fabrication, excellent hydrophobicity, superior antibacterial activity, and biocompatibility and biosafety of the Bi QD/PDMS-modified tooth, it is envisioned that the Bi QD/PDMS-modified tooth with a fascinating self-cleaning and antibacterial performance can pave the way to new designs of versatile multifunctional nanocomposites to prevent secondary caries in the application of dental restoration.