一类具有Neumann边界条件的曲率方程解的估计

研究了一类具有Neumann边界条件的抛物方程解的性质,通过微分方法得到了一类边值问题解的估计,并得到了拟线性方程解的存在性.     

Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling

Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.Subject terms: Translational research, Acute myeloid leukaemia     

Design,Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains

A series of triazole derivatives containing phenylethynyl pyrazole moiety as side chain were designed, synthesized, and most of them exhibited good in vitro antifungal activities. Especially, compounds 5k and 6c showed excellent in vitro activities against C. albicans (MIC = 0.125, 0.0625 μg/mL), C. neoformans (MIC = 0.125, 0.0625 μg/mL), and A. fumigatus (MIC = 8.0, 4.0 μg/mL). Compound 6c also exerted superior activity to compound 5k and fluconazole in inhibiting hyphae growth of C. albicans and inhibiting drug-resistant strains of C. albicans, and it could reduce fungal burdens in mice kidney at a dosage of 1.0 mg/kg. An in vivo efficacy evaluation indicated that 6c could effectively protect mice models from C. albicans infection at doses of 0.5, 1.0, and 2.0 mg/kg. These results suggested that compound 6c deserves further investigation.     

气相生长氮化铝单晶的新方法

通过在钨坩埚盖开小孔的方法改变氮化铝结晶衬底上的温度场分布,在开孔处形成局部低温区;由于孔的几何尺寸的限制和氮化铝晶体生长的各向异性,开孔处的氮化铝晶体单晶化;随后,开孔处的单晶起籽晶的作用,逐渐长成较大尺寸、较高质量的氮化铝单晶.目前用该方法已经制备出直径大于2mm的氮化铝单晶体.     

Separation of pyrrolidine from tetrahydrofuran by using pillar[6]arene-based nonporous adaptive crystals

Pyrrolidine, an important feedstock in the chemical industry, is commonly produced via vapor-phase catalytic ammoniation of tetrahydrofuran (THF). Obtaining pyrrolidine with high purity and low energy cost has extremely high economic and environmental values. Here we offer a rapid and energy-saving method for adsorptive separation of pyrrolidine and THF by using nonporous adaptive crystals of per-ethyl pillar[6]arene (EtP6). EtP6 crystals show a superior preference towards pyrrolidine in 50 : 50 (v/v) pyrrolidine/THF mixture vapor, resulting in rapid separation. The purity of pyrrolidine reaches 95% in 15 min of separation, and after 2 h, the purity is found to be 99.9%. Single-crystal structures demonstrate that the selectivity is based on the stability difference of host–guest structures after uptake of THF or pyrrolidine and non-covalent interactions in the crystals. Besides, EtP6 crystals can be recycled efficiently after the separation process owing to reversible transformations between the guest-free and guest-loaded EtP6.

Here we offer a rapid and energy-saving method for adsorptive separation of pyrrolidine and tetrahydrofuran by using nonporous adaptive crystals of per-ethyl pillar[6]arene.

Pyrrolidine is an important feedstock in the chemical industry that has been widely used in the production of food, pesticides, daily chemicals, coatings, textiles, and other materials.¹ Particularly, pyrrolidine is a raw material for organic synthesis of medicines such as buflomedil, pyrrocaine, and prolintane.² Moreover, pyrrolidine is also used as a solvent in the semi-synthetic process of simvastatin, one of the best-selling cardiovascular drugs.³ In the chemical industry, there are many preparation methods for pyrrolidine. The most common way to obtain pyrrolidine is the gas-phase catalytic method using tetrahydrofuran (THF) and ammonia as raw materials;⁴ this is carried out at high temperature under catalysis by solid acids. However, separating pyrrolidine from the crude product is difficult because of similar molecular weights and structures between pyrrolidine (b.p. 360 K and saturated vapor pressure = 1.8 kPa at 298 K) and THF (b.p. 339 K and saturated vapor pressure = 19.3 kPa at 298 K), which result in complicated processes and large energy consumption.⁵ Therefore, it is worthwhile to find energy-efficient and simple methods to separate pyrrolidine from THF.Many techniques and materials, including porous zeolites, metal–organic frameworks (MOFs), and porous polymers, have facilitated energy-efficient separations of important petrochemicals and feedstocks, including THF and pyrrolidine.^6,7 However, some drawbacks of these materials cannot be ignored.⁸ For example, the relatively low thermal and moisture stabilities of MOFs limit their practical applications. Therefore, the development of new materials with satisfactory chemical and thermal stabilities for pyrrolidine/THF separation is of high significance.In the past decade, pillararenes have been widely studied in supramolecular chemistry.⁹ Owing to their unique pillar structures and diverse host–guest recognitions, pillararenes have been used in the construction of numerous supramolecular systems.¹⁰ Recently, nonporous adaptive crystals (NACs) of macrocycles, which have shown extraordinary performance in adsorption and separation, have been developed by our group as a new type of adsorption and separation materials.¹¹ Unlike MOFs, covalent-organic frameworks (COFs), and other materials with pre-existing pores, NACs do not have “pores“ in the guest-free form, whereas they adsorb guest vapors through cavities of macrocycles and spaces between macrocycles. NACs have been applied in separations of many significant chemicals such as alkane isomers, aromatics, and halohydrocarbon isomers.¹² However, such materials have never been used to separate pyrrolidine and THF. Herein, we utilized pillararene crystals as a separation material and realized the selective separation of pyrrolidine from a mixture of pyrrolidine and THF. We found that nonporous crystals of per-ethyl pillar[6]arene (EtP6) exhibited a shape-sorting ability at the molecular level towards pyrrolidine with an excellent preference, while crystals of per-ethyl pillar[5]arene (EtP5) did not (Scheme 1). In-depth investigations revealed that the separation was driven by the host–guest complexation between pyrrolidine and EtP6, which resulted in the formation of a more stable structure upon adsorption of pyrrolidine vapor in the crystalline state. EtP6 crystals can also adsorb THF. However, when these two chemicals simultaneously exist as the vapor of a 50 : 50 (v/v) mixture, EtP6 prefers pyrrolidine as an adsorption target. Compared with previously reported NAC-based separation, this separation took place rapidly. 95% purity was achieved in 15 min, and the purity increased to 99.9% after 2 h of separation. Moreover, pyrrolidine was removed upon heating, along with the structural transformation of EtP6 back to its original state, endowing EtP6 with excellent recyclability.Open in a separate windowScheme 1Chemical structures and cartoon representations: (a) EtP5 and EtP6; (b) THF and pyrrolidine.EtP5 and EtP6 were prepared as previously described and then a pretreatment process was carried out to obtain guest-free EtP5 and EtP6 (Fig. S1–S4†).¹³ According to powder X-ray diffraction (PXRD) patterns, activated EtP5 and EtP6 (denoted as EtP5α and EtP6β, respectively) were crystalline, and the patterns matched previous reports (Fig. S5 and S6^†).¹⁴ Studies from our group indicated that EtP5α and EtP6β crystals were nonporous, presumably due to their dense packing modes.We first investigated the adsorption capabilities of EtP5α and EtP6β towards pyrrolidine and THF vapors. Based on time-dependent solid–vapor adsorption procedures, both EtP5α and EtP6β showed good ability to adsorb pyrrolidine and THF vapors. As shown in Fig. 1a, the adsorption amount of THF in EtP5α was higher than that of pyrrolidine. It took 6 hours for EtP5α to reach saturation points for adsorption of both pyrrolidine and THF vapors. The final storage of THF in EtP5α was 2 : 1 (molar ratio to the host), whereas the storage of pyrrolidine was 1 : 1. It seemed that the THF vapor was favored to occupy EtP5α, which was ascribed to the relatively lower boiling point of THF. A similar phenomenon was found for EtP6β. Time-dependent solid–vapor adsorption experiments for pyrrolidine demonstrated that it took just 1 hour to reach the saturation point, while it took 4 hours for the THF vapor (Fig. 1b). The adsorption amount of THF vapor was twice that of pyrrolidine. ¹H NMR spectra and thermogravimetric analyses (TGA) further confirmed the adsorption and storage of THF and pyrrolidine in both hosts (Fig. S7–S16†). Meanwhile, in the desorption process, adsorbed pyrrolidine and THF in EtP6β were easily released under reduced pressure and heating. Based on these data, it was clear that pyrrolidine could be adsorbed rapidly by both EtP5α and EtP6β in molar ratios = 1 : 1, while THF could be captured in a relatively slow process. Structural changes after adsorption of these two vapors were analyzed via PXRD experiments, in which varying degrees of changes before and after adsorption were observed, evidencing the appearance of new crystal structures (Fig. 1c and d). Nevertheless, only slight differences were observed in the PXRD patterns after the adsorption of THF or pyrrolidine, which might be ascribed to the structural similarity of the two molecules.Open in a separate windowFig. 1Time-dependent solid–vapor adsorption plots of (a) EtP5α and (b) EtP6β for single-component pyrrolidine and THF vapors. PXRD patterns of (c) EtP5α and (d) EtP6β: (I) original activated crystals; (II) after adsorption of THF vapor; (III) after adsorption of pyrrolidine vapor.To study the mechanism of adsorption, guest-loaded single crystals were obtained by slowly evaporating either THF or pyrrolidine solutions of pillararenes (Tables S2 and S3^†). In the crystal structure of THF-loaded EtP5 (2THF@EtP5, Fig. 2a and S17^†),^11a two THF molecules are in the cavity of one EtP5 molecule driven by multiple C–H⋯O hydrogen bonds and C–H⋯π bonds. EtP5 assembles into honeycomb-like infinite edge-to-edge 1D channels. In the crystal structure of pyrrolidine-loaded EtP5 (pyrrolidine@EtP5, Fig. 2b and S19^†), one pyrrolidine molecule, stabilized by C–H⋯π interactions and C–H⋯O hydrogen bonds between hydrogen atoms on pyrrolidine and oxygen atoms on EtP5, is found in the cavity of EtP5. It''s worth mentioning that a hydrogen atom which is linked with the N atom of pyrrolidine also forms a strong hydrogen bond with an oxygen atom on the ethoxy group of EtP5. EtP5 forms imperfect 1D channels because of partial distortion of orientation. The PXRD patterns simulated from these crystal structures matched well with the experimental results (Fig. S18 and S20^†), which verified that the uptake of vapors transformed EtP5α into pyrrolidine-loaded EtP5.Open in a separate windowFig. 2Single crystal structures: (a) 2THF@EtP5; (b) pyrrolidine@EtP5.In the crystal structure of THF-loaded EtP6 (2THF@EtP6, Fig. 3a and S21^†), one EtP6 molecule encapsulated two THF molecules in its cavity with C–H⋯O interactions, forming a 1 : 2 host–guest complex. Although 1D channels are observed, EtP6 adopts a slightly different conformation, caused by the presence of THF. Moreover, the PXRD pattern of EtP6β after adsorption of THF vapor matches well with that simulated from 2THF@EtP6, which is evidence for the structural transformation upon adsorption. In the crystal structure of pyrrolidine-loaded EtP6 (pyrrolidine@EtP6, Fig. 3b and S23^†), a 1 : 1 host–guest complex with pyrrolidine is found. Driven by C–H⋯π interactions and C–H⋯O hydrogen bonds formed by hydrogen atoms on pyrrolidine and oxygen atoms on EtP6, one pyrrolidine molecule is in the cavity of EtP6 with the nitrogen atom inside the cavity. The window-to-window packing mode of hexagonal EtP6 molecules in pyrrolidine@EtP6 contributes to the formation of honeycomb-like infinite edge-to-edge 1D channels, favorable for guest adsorption. Likewise, the PXRD result of EtP6β after adsorption of pyrrolidine is in line with the simulated pattern of pyrrolidine@EtP6, indicating that EtP6β transformed into pyrrolidine@EtP6 in the presence of pyrrolidine (Fig. S22 and S24^†).Open in a separate windowFig. 3Single crystal structures: (a) 2THF@EtP6; (b) pyrrolidine@EtP6.According to the adsorption ability and different crystal structures after adsorption of guest vapors, we wondered whether EtP5α or EtP6β could separate mixtures of THF and pyrrolidine. We first evaluated separation by EtP5α. GC analysis indicated that the adsorption ratios of THF and pyrrolidine were 65.7% and 34.3%, respectively, when EtP5α was exposed to 50 : 50 (v/v) pyrrolidine/THF mixture vapor (Fig. 4a and S25^†). Such adsorption was also illustrated by ¹H NMR (Fig. S26^†). Although EtP5α showed a preference for THF, the selectivity is not satisfactory and cannot be applied to industrial separation. The less satisfactory selectivity may be ascribed to the similar crystal structures of EtP5 after adsorption of THF or pyrrolidine and insufficient strong stabilizing interactions. The PXRD pattern of EtP5α after adsorption of the 50 : 50 (v/v) pyrrolidine/THF mixture vapor exhibited minor differences compared with that simulated from either 2THF@EtP5 or pyrrolidine@EtP5, due to poor selectivity (Fig. 4b).Open in a separate windowFig. 4(a)Time-dependent solid–vapor adsorption plot for EtP5α in the presence of 50 : 50 (v/v) pyrrolidine/THF mixture vapor. (b) PXRD patterns of EtP5α: (I) original EtP5α; (II) after adsorption of THF vapor; (III) after adsorption of pyrrolidine vapor; (IV) after adsorption of pyrrolidine/THF mixture vapor; (V) simulated from the single crystal structure of pyrrolidine@EtP5α; (VI) simulated from the single crystal structure of 2THF@EtP5α. (c) Time-dependent solid–vapor adsorption plot for EtP6β in the presence of 50 : 50 (v/v) pyrrolidine/THF mixture vapor. (d) PXRD patterns of EtP6β: (I) original EtP6β; (II) after adsorption of THF vapor; (III) after adsorption of pyrrolidine vapor; (IV) after adsorption of pyrrolidine/THF mixture vapor; (V) simulated from the single crystal structure of pyrrolidine@EtP6β; (VI) simulated from the single crystal structure of 2THF@EtP6β.Nevertheless, selective separation of THF and pyrrolidine was achieved with EtP6β. As shown in Fig. 4c, time-dependent solid–vapor adsorption experiments for a 50 : 50 (v/v) pyrrolidine/THF mixture were conducted. Unlike the phenomenon in single-component adsorption experiments, uptake of pyrrolidine by EtP6β increased and reached the saturation point rapidly (less than 2 hours), while capture of THF was negligible. According to the NMR and GC results (Fig. S27 and S28^†), the purity of pyrrolidine was determined to be 99.9% after 2 hours of adsorption, which indicates the remarkable selectivity of EtP6β for pyrrolidine. The PXRD pattern of EtP6β after adsorption of the mixture was consistent with that from single-component adsorption, indicating the structural transformation in the crystalline state upon selective capture of pyrrolidine from the mixture. Although THF and pyrrolidine have similar molecular structures, their non-covalent interactions with EtP6 are different. We assume that the hydrogen bond between N–H and the oxygen atom on EtP6 stabilizes pyrrolidine and leads to such selectivity. More importantly, compared with previous adsorption processes using NACs reported by our group, the selective separation of pyrrolidine was completed rapidly. According to the GC results, the purity of pyrrolidine reached around 95% in the initial 15 min, while it usually takes hours for selective separations of other substrates using NACs. Increasing the adsorption time to 2 h improves the purity to over 99%. The rapid separation of pyrrolidine with high purity using EtP6β shows great potential in industrial applications.Apart from selectivity, recyclability is also an important parameter for an adsorbent. Consequently, recycling experiments were carried out by heating pyrrolidine@EtP6 under vacuum at 100 °C to remove adsorbed pyrrolidine. According to TGA and PXRD analysis, the recycled EtP6 solid maintained crystallinity and structural integrity that were the same as those of activated EtP6 crystals (Fig. S29 and S30^†). Besides, it is worth mentioning that the recycled EtP6 solids were still capable of separating mixtures of pyrrolidine and THF without loss of performance after being recycled five times (Fig. S31^†).In conclusion, we explored the separation of pyrrolidine/THF mixtures using NACs of EtP5 and EtP6. Pyrrolidine was purified using EtP6 from a 50 : 50 (v/v) pyrrolidine/THF mixture with a purity of 99.9%, but EtP5 exhibited selectivity towards THF. Moreover, the separation of pyrrolidine by EtP6 was extremely fast so that over 95% purity was determined within 15 min of adsorption. The rapid separation is unique among NAC-based separations. Single-crystal structures revealed that the selectivity depended on the stability of the new structures after adsorption of the guests and the non-covalent interactions in the host–guest complexes. PXRD patterns indicated that the structures of the host crystals changed into the host–guest complexes after adsorption. Additionally, the NACs of EtP6 exhibited excellent recyclability over at least five runs; this endows EtP6 with great potential as an alternative adsorbent for rapid purification of pyrrolidine that can be applied in practical industry. The fast separation with such simple NACs in this work also reveals that minor structural differences can cause significant changes in properties, which should provide perspectives on designs of adsorbents or substrates with specifically tailored binding sites.     

Synthesis, Crystal Structure and Biological Activity of Novel Dichloroacetyl Oxazolidine Herbicide Safeners

A series of novel N-dichloroacetyl oxazolidine herbicide safeners was synthesized and characterized by IR, 1H NMR, 13C NMR, elemental analysis and X-ray diffraction. The preliminary biological test shows that the compounds could protect maize against injury caused by chlorsulfuron to a certain extent.     

Genetically engineered materials: Proteins and beyond

Information-rich molecules provide opportunities for evolution. Genetically engineered materials are superior in that their properties are coded within genetic sequences and could be fine-tuned. In this review, we elaborate the concept of genetically engineered materials(GEMs) using examples ranging from engineered protein materials to engineered living materials. Proteinbased materials are the materials of choice by nature. Recent progress in protein engineering has led to opportunities to tune...     

Quantum Circuit Optimization for Solving Discrete Logarithm of Binary Elliptic Curves Obeying the Nearest-Neighbor Constrained

In this paper, we consider the optimization of the quantum circuit for discrete logarithm of binary elliptic curves under a constrained connectivity, focusing on the resource expenditure and the optimal design for quantum operations such as the addition, binary shift, multiplication, squaring, inversion, and division included in the point addition on binary elliptic curves. Based on the space-efficient quantum Karatsuba multiplication, the number of CNOTs in the circuits of inversion and division has been reduced with the help of the Steiner tree problem reduction. The optimized size of the CNOTs is related to the minimum degree of the connected graph.     

Toxic Effect of Fullerene and Its Derivatives upon the Transmembrane β2-Adrenergic Receptors

Numerous experiments have revealed that fullerene (C₆₀) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the β₂-adrenergic receptor (β₂AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of β₂AR through hydrophobic interactions and π–π stacking interactions. In the C₆₀_in1 trajectory, due to the π–π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of β₂AR. The hydroxyl groups of fullerene derivatives (C₆₀(OH)_X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of β₂AR. The hydroxyl groups firmly grasp the β₂AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of β₂AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C₆₀ did not compete with ligands for binding sites, but blocked the ligands’ entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity.     

Preparation of Silica Aerogel/Resin Composites and Their Application in Dental Restorative Materials

As the most advanced aerogel material, silica aerogel has had transformative industrial impacts. However, the use of silica aerogel is currently limited to the field of thermal insulation materials, so it is urgent to expand its application into other fields. In this work, silica aerogel/resin composites were successfully prepared by combining silica aerogel with a resin matrix for dental restoration. The applications of this material in the field of dental restoration, as well as its performance, are discussed in depth. It was demonstrated that, when the ratio of the resin matrix Bis-GMA to TEGDMA was 1:1, and the content of silica aerogel with 50 μm particle size was 12.5%, the composite achieved excellent mechanical properties. The flexural strength of the silica aerogel/resin composite reached 62.9546 MPa, which was more than five times that of the pure resin. Due to the presence of the silica aerogel, the composite also demonstrated outstanding antibacterial capabilities, meeting the demand for antimicrobial properties in dental materials. This work successfully investigated the prospect of using commercially available silica aerogels in dental restorative materials; we provide an easy method for using silica aerogels as dental restorative materials, as well as a reference for their application in the field of biomedical materials.