Computational Insights into a CO2-Responsive Emulsion Prepared Using the Superamphiphile Assembled by Electrostatic Interactions.

The superamphiphiles exhibit broad prospects for fabricating stimuli-responsive emulsions. Because the superamphiphiles are assembled via noncovalent interactions, they have the advantage of fast response and high efficiency. Recently, a series of switchable emulsions using CO2-responsive superamphiphiles have been developed, which extends the applications of CO2-responsive materials in widespread field. However, there is still a lack of fundamental understanding on the switching mechanism related to the assembled structure of superamphiphiles at the oil-water interface. We employed molecular dynamics (MD) simulations to investigate the reversible emulsification/demulsification process of a responsive emulsion system stabilized by a recently developed responsive superamphiphile (BTOA), which consists of oleic acid (OA) and cationic amine (named 1,3-bis(aminopropyl)tetramethyldisiloxane, BT). The simulation results present the morphologies in both the emulsion and demulsification states. It is found that the ionized OA- and the protonated BT+ together form an adsorption layer at the oil-water interface. The hydrophobic parts of BT+ are inserted into the adsorption layer, and the two amine groups contact the water phase. This adsorption layer reduces the interfacial tension and stabilizes the emulsion. After the bubbling of CO2, the surfactants were fully protonated to OA and BT2+. Because of the changes in the molecular polarity, OA and BT2+ entered the oil and water phases, respectively, resulting in demulsification. The structural and dynamical properties were analyzed to reveal the different intermolecular interactions that were responsible for the reversible reversibility of the emulsion. The observations are considered to be complementary to experimental studies and are expected to provide deeper insights into studies on developing responsive materials via supramolecular assemblies.

Cosmetically Approved Short-Chain Alcohol/Triethyl Citrate/Water Surfactant-Free Microemulsions and Potential Application to Transdermal Penetration of α-Arbutin.

Surfactant-free microemulsions (SFMEs) exhibited remarkable advantages and potential, attributed to their similarity to traditional surfactant-based microemulsions and the absence of surfactants. Herein, a novel SFME was developed utilizing cosmetically approved materials, such as short-chain alcohol as an amphi-solvent, triethyl citrate (TEC) as the nonpolar phase, and water as the polar phase. 1,2-Pentanediol (PtDO)/TEC/water combination can form the largest monophasic zone, accounting for ∼74% of the total phase diagram area, due to an optimal hydrophilic (water)-lipophilic (TEC) balance. Comparable to surfactant-based microemulsion, PtDO/TEC/water SFME can also be categorized into three types: water-in-oil, discontinuous, and oil-in-water. As TEC or water is increased, or PtDO is decreased, the nanoaggregates in PtDO/TEC/water SFME grow from <5 nm to tens of nanometers. The addition of α-arbutin (ABN) does not disrupt PtDO/TEC/water SFME, but rather enhances its formation, resulting in a larger monophasic area and consistent size (2.8-3.8 nm) through participating in interface assembly. Furthermore, ABN-loaded PtDO/TEC/water SFME exhibits remarkable resistance to dilution, exceptional stability, and minimal irritation. Notably, PtDO/TEC/water SFME significantly boosts ABN's solubility in water by 2 times, its percutaneous penetration rate by 3-4 times, and enables a slow-release DPPH• radical scavenging effect. This SFME serves as a safe and cosmetically suitable nanoplatform for the delivery of bioactive substances.

Old trees bloom new flowers, lysosome targeted near-infrared fluorescent probe for ratiometric sensing of hypobromous acid in vitro and in vivo based on Nile red skeleton.

Hypobromous acid (HOBr), one of the significant reactive oxygen species (ROS) that acts as an important role in human immune system, however the increasing level of HOBr in human body can cause the disorder of eosinophils (EPO), leading to oxidative stress in organelles, and further causing a series of diseases. In this study, a ratiometric fluorescent probe DMBP based on Nile red skeleton was developed to detect HOBr specifically by the electrophilic substitution with HOBr. DMBP emits near-infrared (NIR) fluorescence at 653 nm, after reacting with HOBr, the emission wavelength of DMBP shifted blue and a new peak appeared at 520 nm, realizing a ratiometric examination of HOBr with a limit of detection of 89.00 nM. Based on its sensitive and specific response to HOBr, DMBP was applied in the visual imaging of HOBr in HepG2 cells and zebrafish. Foremost, probe DMBP has excellent lysosome targeting ability and NIR emission reduced the background interference of biological tissues, providing a potential analytical tool to further investigate the role of HOBr in lysosome.

How does full-cost insurance for wheat affect pesticide use? From the perspective of the differentiation of farmers' production scale.

Theoretically, agricultural insurance influences farmers' use of pesticides by changing the expected income of agricultural production. Full-cost insurance, with high guarantee and high compensation characteristics, may significantly affect farmers' pesticide use. First, this paper constructs a production function to characterize and compare the marginal incomes of insured and uninsured farmers under risk uncertainty and analyses how insured farmers can increase marginal income by increasing or reducing factor inputs. Considering scale differentiation, it discusses pesticide use strategies different types of farmers may adopt to maximize household utility. Second, using survey data of the pilot counties of full-cost insurance for wheat in Henan Province, China, the simultaneous equation model is used for empirical testing. The results reveal the following: (i) Farmers' insurance participation and pesticide application behaviour are not mutually independent. (ii) For the whole sample, full-cost insurance for wheat has a significant pesticide reduction effect. (iii) However, considering scale differentiation, pesticide application decreases significantly among insured ordinary farmers but does not change significantly among insured large-scale farmers. Third, policy measures are proposed to activate the green development function of agricultural insurance.

Synthesis of Novel Pentacyclic Triterpenoid Derivatives that Induce Apoptosis in Cancer Cells through a ROS-dependent, Mitochondrial-Mediated Pathway.

Betulinic acid (BA) and oleanolic acid (OA) are plant-derived conjugates found in various medicinal plants that have emerged as potential antitumor agents. Herein, a series of novel BA and OA derivatives were synthesized by conjugation with per-O-methylated-ß-cyclodextrin (PM-ß-CD), and their anticancer properties against a panel of three human cancer cell lines were evaluated. Two OA-PM-ß-CD conjugates (48 and 50) were observed to be the most potent conjugates against the three cell lines (MCF-7, BGC-823, and HL-60), with a 15- to 20-fold decrease in the IC50 values (IC50: 6.06-8.47 µM) compared with their parental conjugate (OA). Annexin V-FITC/propidium iodide staining and Western blot analysis revealed that both conjugates induced apoptosis in HL-60 cells. Additionally, in the representative conjugate 48-treated HL-60 cells, a decrease in mitochondrial membrane potential and subsequent release of cytochrome c into the cytosol were observed, indicating the activation of the intrinsic apoptosis pathway. Furthermore, 48 dramatically induced the generation of reactive oxygen species (ROS) in HL-60 cells, and the corresponding effect could be reversed using the ROS scavenger N-acetylcysteine. Collectively, these results suggest that the novel pentacyclic triterpenoid derivatives trigger the intrinsic apoptotic pathways via the ROS-mediated activation of caspase-3 signaling, inducing cell death in human cancer cells.

Molecular Insight into the Pozzolanic Reaction of Metakaolin and Calcium Hydroxide.

The reaction mechanism of the pozzolanic reaction of metakaolin (MK) from the atomic point of view has not yet been explored. To explain the process and mechanism of the pozzolanic reaction from the atomic point of view, molecular insight into the pozzolanic reaction of MK and calcium hydroxide (CH) was analyzed through the reaction molecular dynamics (MD) simulation. The results show that the pozzolanic reaction of MK and CH can be essentially regarded as the CH decomposition and penetration into MK. Also, the structure evolution after the pozzolanic reaction shows that the water molecules cannot penetrate the MK structure till the participation of Ca2+ and OH- ions of CH. The Ca2+ and OH- ions have strong interaction with MK and drill into the MK structure, followed by the destruction of a part of the MK structure and water penetration. The final structure of CH removed by MK can be regarded as the precursor of the CASH gel structure.

FAK/IL-8 axis promotes the proliferation and migration of gastric cancer cells.

Gastric cancer (GC) is one of the most common malignancies in China and is associated with high mortality. The occurrence and development of gastric cancer are related to genetic and environmental factors. Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor protein tyrosine kinase that is activated by the extracellular matrix and growth factors. FAK is highly expressed in cancer and promotes its development by regulating cancer cell proliferation, migration, and angiogenesis. The expression of IL-8 is increased in many types of malignant tumor cells and is linked to their proliferation, migration, invasion, angiogenesis, and EMT. In this study, we found FAK to be essential for the proliferation, migration, and peritoneal metastasis of gastric cancer cells. To examine the molecular regulatory mechanisms of FAK in the peritoneal dissemination of gastric cancer, we performed RNA-seq analysis of MKN-45-FAK-/- and MKN45 cells and demonstrated that IL-8 was downregulated in FAK-deficient cells. Conversely, we confirmed that IL-8 activates FAK activity. We established that IL-8 promotes the proliferation, colony formation, and migration of gastric cancer cells that are partially mediated by FAK. Thus, we propose that an IL-8-FAK-IL-8 positive feedback loop effects the proliferation and migration of gastric cancer cells.

Research Progress on Bacterial Membrane Vesicles and Antibiotic Resistance.

As a result of antibiotic overuse, bacterial antibiotic resistance has become a severe threat to worldwide public health. The development of more effective antimicrobial therapies and alternative antibiotic strategies is urgently required. The role played by bacterial membrane vesicles (BMVs) in antibiotic resistance has become a current focus of research. BMVs are nanoparticles derived from the membrane components of Gram-negative and Gram-positive bacteria and contain diverse components originating from the cell envelope and cytoplasm. Antibiotic stress stimulates the secretion of BMVs. BMVs promote and mediate antibiotic resistance by multiple mechanisms. BMVs have been investigated as conceptually new antibiotics and drug-delivery vehicles. In this article, we outline the research related to BMVs and antibiotic resistance as a reference for the intentional use of BMVs to combat antibiotic resistance.

Controlled Decoration of [60]Fullerene with Polymannan Analogues and Amino Acid Derivatives through Malondiamide-Based Linkers.

In the last few years, nanomaterials based on fullerene have begun to be considered promising tools in the development of efficient adjuvant/delivery systems for vaccination, thanks to their several advantages such as biocompatibility, size, and easy preparation and modification. In this work we reported the chemoenzymatic synthesis of natural polymannan analogues (di- and tri-mannan oligosaccharides characterized by α1,6man and/or α1,2man motifs) endowed with an anomeric propargyl group. These sugar derivatives were submitted to 1,3 Huisgen dipolar cycloaddition with a malondiamide-based chain equipped with two azido terminal groups. The obtained sugar-modified malondiamide derivatives were used to functionalize the surface of Buckminster fullerene (C60) in a highly controlled fashion, and yields (11-41%) higher than those so far reported by employing analogue linkers. The same strategy has been exploited to obtain C60 endowed with natural and unnatural amino acid derivatives. Finally, the first double functionalization of fullerene with both sugar- and amino acid-modified malondiamide chains was successfully performed, paving the way to the possible derivatization of fullerenes with immunogenic sugars and more complex antigenic peptides.

Facial Synthesis and Bioevaluation of Well-Defined OEGylated Betulinic Acid-Cyclodextrin Conjugates for Inhibition of Influenza Infection.

Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa-, hepta- and octavalent BA derivatives based on α-, ß- and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave-assisted copper-catalyzed 1,3-dipolar cycloaddition reaction. The generated BA-cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested compounds, 58, 80 and 82 showed slight cytotoxicity to Madin-Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 µM. Four conjugates 51 and 69-71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration values of 5.20, 9.82, 7.48 and 7.59 µM, respectively. The structure-activity relationships of multivalent BA-cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection.

COVID-19 impact on commodity futures volatilities.

COVID-19 pandemic has affected almost all aspects of the global economy, especially commodity futures markets, due to the disruption risk of global supply chains from the pandemic lockdown. This paper extends ARMA-GARCH models to investigate the pandemic impact on both long-run and short-term volatilities of four major commodity futures. Model-fitting results reveal that the pandemic event has enhanced long-run volatilities for all futures returns, while the daily COVID-19 infection speed has mixed effects on short-term (instantaneous) volatilities. Our extended models and research findings are useful in global supply chain risk management, commodity options trading and regulators' supervision of inflation risk.

Mapping C-H⋠⋠⋠M Interactions in Confined Spaces: (α-ICyDMe )Au, Ag, Cu Complexes Reveal "Contra-electrostatic H Bonds" Masquerading as Anagostic Interactions*.

What happens when a C-H bond is forced to interact with unpaired pairs of electrons at a positively charged metal? Such interactions can be considered as "contra-electrostatic" H-bonds, which combine the familiar orbital interaction pattern characteristic for the covalent contribution to the conventional H-bonding with an unusual contra-electrostatic component. While electrostatics is strongly stabilizing component in the conventional C-H⋅⋅⋅X bonds where X is an electronegative main group element, it is destabilizing in the C-H⋅⋅⋅M contacts when M is Au(I), Ag(I), or Cu(I) of NHC-M-Cl systems. Such remarkable C-H⋅⋅⋅M interaction became experimentally accessible within (α-ICyDMe )MCl, NHC-Metal complexes embedded into cyclodextrins. Computational analysis of the model systems suggests that the overall interaction energies are relatively insensitive to moderate variations in the directionality of interaction between a C-H bond and the metal center, indicating stereoelectronic promiscuity of fully filled set of d-orbitals. A combination of experimental and computational data demonstrates that metal encapsulation inside the cyclodextrin cavity forces the C-H bond to point toward the metal, and reveals a still attractive "contra-electrostatic" H-bonding interaction.

Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease*.

Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and ß-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured ß-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

Oxidation-Induced Breakage of the Imine Bond and Aggregate Transition in a Se-Containing Dynamic Covalent Surfactant.

Controlling the dynamic imine bonds upon a novel trigger except for pH and temperature is still a significant challenge. Here, a Se-containing imine-based dynamic covalent surfactant (HOBAB-BSeEA) was developed for the first time by mixing two precursors in situ: an asymmetric double-chain cationic surfactant bearing a formyl group at the terminal of one hydrophobic tail and a Se-containing amine (2-(benzylselanyl)ethan-1-amine) in order to confirm the effect of redox on the imine bonds. The imine bond in HOBAB-BSeEA can be regulated not only upon changing the pH as well as other common imine-based surfactants but also by oxidation. The conversion efficiency of imine bonds is closely related with the degree of oxidation and pH. Complete oxidation can decrease the conversion efficiency from ∼87 to 48%, which is comparable to the result of changing the pH from 10.0 to 7.0. With the formation and breaking of imine bonds, the surfactant can be reversibly switched between symmetric and asymmetric structures, accompanied by a morphological transition from vesicles to spherical micelles. Although oxidation cannot demolish all imine bonds, it can completely convert vesicles to spherical micelles, which is mainly ascribed to an increase in the polarity of the micellar microenvironment stemming from the oxidation of Se. However, this transition can only be achieved by reducing the pH to 5.0 instead of 7.0. Nile red loaded in HOBAB-BSeEA vesicles can be quickly, controllably, and step-by-step released upon oxidation stimulus but not pH. Understanding the mechanism of oxidation-induced breakage of imine bonds and disruption of vesicles would be useful in designing redox-responsive imine-based carriers that can unload cargoes according to the level of the local reactive oxygen species.

CO2 and Temperature Control over Nanoaggregates in Surfactant-Free Microemulsion.

Smart microemulsions (MEs) recently have attracted significant interests. However, MEs, especially surfactant-free MEs (SFMEs) that respond to more than one stimulus, are rarely reported to date. Here, we reported the first example of dual-responsive SFME in which a CO2-sensitive hydroxyethylamine was used as an amphisolvent. This SFME was investigated utilizing ternary phase diagram, dynamic light scattering, and UV-visible spectrum techniques. It was found that three hydroxyethylamines could stabilize the octanol-water mixture to form transparent and isotropic SFMEs including nanoaggregates-rich pre-ouzo zone, regardless of the number of the hydroxyl group. Among them, 2-(dimethyl amino) ethanol (DMEA)-based SFME possesses the largest single-phase region and most sensitive to CO2 and the changes in temperature. With bubbling of CO2/N2 or decreasing/increasing temperature, both the single-phase region and pre-ouzo zone reversibly shrink and expand, as well as with breathing. However, CO2/N2-induced change is more significant than that induced by temperature. The former is mainly ascribed to the reversible protonation and deprotonation of DMEA, while the latter is generally interpreted as the effects of temperature on hydrogen bond interaction. Note that CO2 leads to a thorough demusification from Winsor IV ME to oil-rich and water-rich two phases without nanoaggregates, while cooling only causes to a particular phase separation, producing two new MEs phases, not typical Winsor I or II MEs. Such a unique dual-responsive SFME can not only be applied in the remediation of contaminated soil, drug delivery, and nanoparticles preparation but also opens a new door to switchable emulsion.

Effects of different personalised sound therapies in tinnitus patients with hearing loss of various extents.

BACKGROUND: Limited by difficulties in choosing the appropriate sound, sound therapies could only effectively restrain the development of tinnitus in some patients. Thus, individualised sound therapies are of urgent needs. OBJECTIVE: The purpose of this study was to determine the therapeutic effect of different individualised sound therapies in tinnitus patients complicated with hearing loss of various extents. RESEARCH DESIGN: Participants were assigned to two different personalised sound therapies as counterbalanced by age and gender in this observational study. STUDY SAMPLE: Ninety-two tinnitus patients with hearing loss admitted to our hospital from January 2018 to January 2020 were enrolled and evenly grouped as the observation group and the control group in accordance with the random number table. DATA COLLECTION AND ANALYSES: Tinnitus characteristics of both the groups were determined before treatment. Patients from the observation group received pure tone sound therapy composed of 7 octaves (0.125, 0.25, 0.5, 1, 2, 4 and 8 kHz) based on frequencies determined from their tinnitus characteristics. The control group received pure tone sound therapy composed of 9 one-third octaves based on their tinnitus characteristics. RESULTS: The observation group had better therapeutic effects than that in the control group (91.30% vs 73.91%, P < .05). After 1 week, and 1- to 3-month treatment, patients in the observation group all presented with decreased tinnitus handicap, decreased tinnitus volume and improved sleep quality compared with the control group (P < .05). CONCLUSION: This study found that both personalised sound therapies were effective in tinnitus treatment while 7-octave pure tone adjusted from tinnitus frequencies were more promising in decreasing tinnitus handicap and tinnitus volume.

Programmed Synthesis of Hepta-Differentiated ß-Cyclodextrin: 1 out of 117655 Arrangements.

Cyclodextrin poly-functionalization has fueled progress in their use in multiple applications such as enzyme mimicry, but also in the polymer sciences, luminescence, as sensors or for biomedical applications. However, regioselective access to a given pattern of functions on ß-cyclodextrin is still very limited. We uncover a new orienting group, the thioacetate, that expands the toolbox available for cyclodextrin poly-hetero-functionalization using diisobutylaluminum hydride (DIBAL-H) promoted debenzylation. The usefulness of this group is illustrated in the first synthesis of a precisely hepta-hetero-functionalized ß-cyclodextrin. By way of comparison, a random hepta-functionalization would give 117655 different molecules. This synthesis is not simply the vain quest for the Holy Grail of CD hetero-functionalization, but it illustrates the versatility of the DIBAL-H oriented hetero-functionalization strategy, opening the way to a multitude of useful functionalization patterns for new practical applications.

Permethylated NHC-Capped α- and ß-Cyclodextrins (ICyDMe ) Regioselective and Enantioselective Gold-Catalysis in Pure Water.

A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped permethylated cyclodextrins (ICyDMe ) were developed and used as catalysts in pure water for hydration, lactonization, hydroarylation and cycloisomerization reactions. ICyDMe ligands gave cavity-based high regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions giving up to 98 % ee in water. These ICyDMe are therefore useful ligands for selective catalysis in pure water.

Synthesis of a Hexavalent Betulinic Acid Derivative as a Hemagglutinin-Targeted Influenza Virus Entry Inhibitor.

Naturally occurring pentacyclic triterpenes, such as betulinic acid (BA) and its derivatives, exhibit various pharmaceutical activities and have been the subject of great interest, in particular for their antiviral properties. Here, we found a new anti-influenza virus conjugate, hexakis 6-deoxy-6-[4-N-(3ß-hydroxy-lup-20(29)-en-28-oate)aminomethyl-1H-1,2,3-triazol-1-yl]-2,3-di-O-acetyl-α-cyclodextrin (CYY1-11, 1), in a mini library of pentacyclic triterpene-cyclodextrin conjugates by performing a cell-based screening assay and then exploring the underlying mechanisms. Our results showed that conjugate 1 possessed a high-level activity against the influenza virus A/WSN/33 with an IC50 value of 5.20 µM (SI > 38.4). The study of the mechanism of action indicated that conjugate 1 inhibited viral replication by directly targeting the influenza hemagglutinin protein (KD = 1.50 µM), thus efficiently preventing the attachment of the virion to its receptors on host cells and subsequent infection. This study suggests that multivalent BA derivatives have possible use as a new class of influenza virus entry inhibitors.

Temperature-Switchable Surfactant-Free Microemulsion.

Stimuli-responsive microemulsions have recently attracted significant interest due to their unique properties. Here, we developed a novel surfactant-free microemulsion (SFME) in a nontoxic ternary mixture, in which dimethyl sulfoxide (DMSO) was used as an amphisolvent, n-butanol was used as a nonpolar phase, and water was used as a polar phase. The DLS results confirmed the presence of the preouzo zone, and the polarity experiment revealed that the single-phase region can be further divided into oil-in-water, bicontinuous, and water-in-oil subregions. The size of droplets increased upon increasing the water or n-butanol content but decreased with increasing DMSO content. With increasing temperature, the area of the single-phase region increased, accompanied by a decrease in the size of the droplets, and the critical point moved to the corner of n-butanol. No matter in what subregion the formulation was found, decreasing temperature to below the phase-transition temperature (PTT) will induce a transition from monophasic MEs to complete phase separation and vice versa. This is mainly attributed to the effect of temperature on the hydrogen-bond interaction. Ag nanoparticles (Ag NPs) can be prepared above the PTT and facilely separated below PTT. The Ag NPs obtained from the current SFME showed higher catalytic activity than that obtained from a common surfactant-based ME.