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As a promising antitumor strategy, combination oncotherapy can achieve better therapeutic efficacy. However, given the different properties of drugs, carriers need to meet requirements for efficient encapsulation and controllable release of multi-drugs. Herein, we propose a graphene oxide (GO)-templated biomineralization nanosystem to optimize oncotherapy. For preparation, GO is conjugated with polyethylene glycol (PEG) to improve biostability, and glyeyrrhetinic acid (GA) is further grafted onto PEG chains for site-specific targeting. The generated nanosheet structure and large specific surface area support high doxorubicin (DOX) encapsulation and mineralized deposition of siRNA via π-π stacking and calcium phosphate co-precipitation, respectively. Followed by highly efficient penetration into tumor cells, GO-templated nanosystem performs swift drug release in response to tumor acidic microenvironment through dissolution of calcium phosphate and disruption of molecular interactions. After administration, the GO-templated nanosystem performs superior pharmacy properties and significant antitumor efficacy via the synergy of chemotherapy and RNA interference therapy. Collectively, a GO-templated biomineralization nanosystem provides an innovative delivery system for multi-drug administration in combinative tumor therapy. [ABSTRACT FROM AUTHOR]

The tetrel-bonded complexes formed between the selected boron-substituted carbenes and TH3F (T = C, Si, Ge, Sn, Pb) have been explored by using the high-level quantum chemical method. The binding sites of TH3F in the complexes are generally consistent with the positions of VS,min points of the carbenes, and the -Eint values of the complexes exhibit a general increasing tendency with the increase of the -VS,min values of the carbenes for a given TH3F. The complexes can be divided into the type-I and type-II groups. The type-I complexes are characterized by the 3c(B-C-B)→BD*(T-F) and BD(B-C)→BD*(T-F) orbital interactions, and the type-II complexes are characterized by the LP(C)→BD*(T-F) orbital interactions. The type-II complexes have more negative Eint values than the type-I complexes. The -Eint values of the type-I complexes exhibit a roughly increasing tendency with the increase of the T atomic number, and the -Eint values go in the order SnH3F > PbH3F > GeH3F > SiH3F > CH3F for most type-I complexes, which is consistent with the order of VS,max values of TH3F. Unlike type-I complexes, the -Eint values of the type-II complexes exhibit a zigzag tendency with the increase of the T atomic number, and the -Eint values go in the order SiH3F > SnH3F > GeH3F > PbH3F > CH3F for type-II complexes. The AIM and SAPT analysis has been employed to explore the nature of the intermolecular interactions in these complexes. [ABSTRACT FROM AUTHOR]

Cartilage damage affects millions of people worldwide. Tissue engineering strategies hold the promise to provide off‐the‐shelf cartilage analogs for tissue transplantation in cartilage repair. However, current strategies hardly generate sufficient grafts, as tissues cannot maintain size growth and cartilaginous phenotypes simultaneously. Herein, a step‐wise strategy is developed for fabricating expandable human macromass cartilage (macro‐cartilage) in a 3D condition by employing human polydactyly chondrocytes and a screen‐defined serum‐free customized culture (CC). CC‐induced chondrocytes demonstrate improved cell plasticity, expressing chondrogenic biomarkers after a 14.59‐times expansion. Crucially, CC‐chondrocytes form large‐size cartilage tissues with average diameters of 3.25 ± 0.05 mm, exhibiting abundant homogenous matrix and intact structure without a necrotic core. Compared with typical culture, the cell yield in CC increases 2.57 times, and the expression of cartilage marker collagen type II increases 4.70 times. Transcriptomics reveal that this step‐wise culture drives a proliferation‐to‐differentiation process through an intermediate plastic stage, and CC‐chondrocytes undergo a chondral lineage‐specific differentiation with an activated metabolism. Animal studies show that CC macro‐cartilage maintains a hyaline‐like cartilage phenotype in vivo and significantly promotes the healing of large cartilage defects. Overall, an efficient expansion of human macro‐cartilage with superior regenerative plasticity is achieved, providing a promising strategy for joint regeneration. [ABSTRACT FROM AUTHOR]

The intermolecular complexes formed between imidazol-2-ylidene and its heavy-atom analogues C2H4N2X: (X = C, Si, Ge, Sn, Pb) and YH3F (Y = Si, Ge, Sn, Pb) have been optimized at the MP2/aug-cc-pVTZ level. C2H4N2X: have two electron-rich moieties, one of which is the lone pair on the X atom and the other is the 6π-electron system. Three types of binding modes (type-A, type-B and type-C) can be distinguished for C2H4N2X: according to the locations of YH3F. The type-A and type-B complexes can be located for C2H4N2C:···YH3F system, and the Eint values of the type-A complexes are much larger than those of the type-B complexes. The type-A, type-B and type-C complexes can be located for the other four systems, and the Eint values of these complexes go in the order type-B > type-C > type-A. The binding strength of the type-A complexes becomes weaker, and that of the type-B and type-C complexes becomes stronger with the increase of the X atomic number for C2H4N2X:···YH3F system, which can be clarified by the MEP maps of C2H4N2X:. The NBO, AIM and SAPT analysis was employed to explore the nature of the interactions in these complexes. [ABSTRACT FROM AUTHOR]

The dual binding behavior of the metallylenes TH2 (T = Si, Ge, Sn, Pb) with some selected Lewis acids (T'H3F, T' = Si, Ge, Sn, Pb) and bases (N2, HCN, CO, and C6H6) has been investigated by using the high-level quantum chemical method. Two types (type-A and type-B) of tetrel-bonded complexes can be formed for TH2 due to their ambiphilic character. TH2 act as Lewis bases in type-A complexes, and they act as Lewis acids in type-B ones. CO exhibits two binding modes in the type-B complexes, one of which is TH2···CO and the other is TH2···OC. The TH2···OC complexes possess a weaker binding strength than the other type-B complexes. The TH2···OC complexes are referred to as the type-B2 complexes, and the other type-B complexes are referred to as the type-B1 complexes. The type-A complexes exhibit a relatively weak binding strength with Eint (interaction energy) values ranging from –7.11 to –15.55 kJ/mol, and the type-B complexes have a broad range of Eint values ranging from −9.45 to −98.44 kJ/mol. The Eint values of the type-A and type-B1 complexes go in the order SiH2 > GeH2 > SnH2 > PbH2. The AIM (atoms in molecules) analysis suggests that the tetrel bonds in type-A complexes are purely closed-shell interactions, and those in most type-B1 complexes have a partially covalent character. The EDA (Energy decomposition analysis) results indicate that the contribution values of the three energy terms go in the order electrostatic > dispersion > induction for the type-A and type-B2 complexes, and this order is electrostatic > induction > dispersion for the type-B1 complexes. [ABSTRACT FROM AUTHOR]

Methods: The intermolecular interactions between the heavy-atom analogues of acetylene T2H2 (T = Si, Ge, Sn, Pb) and HCN have been investigated by theoretical calculations at the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVDZ level. Results: The global energy minimum of T2H2 is the butterfly structure A, and another energy minimum is the planar structure B. Both structures A and B exhibit the dual behavior when binding with HCN. The various hydrogen bond (HB), dihydrogen bond (DB) and tetrel bond (TB) complexes can be found according to the MEP maps of T2H2. One TB and three HB complexes formed between structure A and HCN can be located for Si2H2 and Ge2H2. One TB, two HB and one DB complexes formed between structure A and HCN can be located for Sn2H2 and Pb2H2. Four TB and one HB complexes formed between structure B and HCN can be located for all the T2H2. The geometries and binding strengths of the complexes are compared and analyzed. Conclusions: The interactions in these complexes are generally weak, and the interaction energies of these complexes range from −0.53 to −8.23 kcal/mol. The interaction energies of the TB complexes are larger than those of the corresponding HB and DB complexes for structure A···HCN systems. The relative binding strength of the four TB complexes exhibits different order for different structure B···HCN systems, which is consistent with the MEP maps of the isolated monomers. [ABSTRACT FROM AUTHOR]

Background: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure.Methods: We detected the expression of autophagy markers in FLT3-ITD-positive leukemic cells after vs. before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance.Results: Sorafenib-resistant cells markedly overpresented autophagy markers in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to mediate FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame resistance to FLT3 inhibitors.Conclusions: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance. [ABSTRACT FROM AUTHOR]

The goal of this study was twofold: firstly, to investigate vocational accounting students' attitudes towards sustainable development; secondly, to explore the influence of students' professional scepticism on their attitudes towards sustainable development. We surveyed 363 accounting students enrolled in a vocational college in China. We found that students had the most favourable attitudes towards the educational dimension of sustainable development and the least favourable attitudes towards the social dimension. Female students had significantly more favourable attitudes towards the environmental and educational dimensions of sustainable development, as compared to male students. Students at higher academic levels had significantly more favourable attitudes towards the educational dimension of sustainable development, as compared to students at lower academic levels. We also found that the questioning mind dimension of professional scepticism played the largest role in fostering the students' favourable attitudes towards sustainable development, followed by the search for knowledge and interpersonal understanding dimensions, then by the suspension of judgement, self-confidence, and self-determining dimensions. The results of this study provide insights for educators to improve the accounting curriculum in vocational higher education in China. [ABSTRACT FROM AUTHOR]

Articular cartilage damage caused by sports injury or osteoarthritis (OA) has gained increased attention as a worldwide health burden. Pharmaceutical treatments are considered cost-effective means of promoting cartilage regeneration, but are limited by their inability to generate sufficient functional chondrocytes and modify disease progression. Small molecular chemical compounds are an abundant source of new pharmaceutical therapeutics for cartilage regeneration, as they have advantages in design, fabrication, and application, and, when used in combination, act as powerful tools for manipulating cellular fate. In this review, we present current achievements in the development of small molecular drugs for cartilage regeneration, particularly in the fields of chondrocyte generation and reversion of chondrocyte degenerative phenotypes. Several clinically or preclinically available small molecules, which have been shown to facilitate chondrogenesis, chondrocyte dedifferentiation, and cellular reprogramming, and subsequently ameliorate cartilage degeneration by targeting inflammation, matrix degradation, metabolism, and epigenetics, are summarized. Notably, this review introduces essential parameters for high-throughput screening strategies, including models of different chondrogenic cell sources, phenotype readout methodologies, and transferable advanced systems from other fields. Overall, this review provides new insights into future pharmaceutical therapies for cartilage regeneration. [ABSTRACT FROM AUTHOR]

Can preoperative or perioperative intervention reduce the risk of recurrence of endometriosis caused by either incomplete excision or spillage and dissemination? A mouse model of endometriosis recurrence caused by spillage and dissemination was first established using 24 female Balb/c mice. The spillage and dissemination model was used to test the efficacy of preoperative use of ketorolac, perioperative use of aprepitant and combined use of propranolol and andrographolide in a prospective, randomized mouse experiment involving 75 mice. The efficacy of these preoperative and perioperative interventions in a mouse recurrence model caused by incomplete excision was also tested using 72 mice. In all experiments, the baseline body weight and hotplate latency of all mice were measured and recorded before the induction of endometriosis, before the primary surgery and before sacrifice. In addition, all lesions were excised, weighed and processed for quantification and immunohistochemistry analysis of E-cadherin, α-SMA, VEGF, ADRB2 and putative markers of recurrence PR-B, p-p65, as well as Masson trichrome staining. All interventions substantially and significantly suppressed the outgrowth of endometriotic lesions and reduced the risk of recurrence caused by either spillage and dissemination or incomplete excision (P = 0.0007 to 0.042). These interventions also significantly attenuated the generalized hyperalgesia, inhibited the staining of α-SMA, p-p65, VEGF and ADRB2 but increased staining of E-cadherin and PR-B, resulting in reduced fibrosis. Given the excellent safety profiles of these drugs, these data strongly suggest that preoperative and perioperative intervention may potentially reduce the risk of endometriosis recurrence effectively. [ABSTRACT FROM AUTHOR]

The intermolecular interactions between the heavy alkenes H2Si = TH2 (T = C, Si, Ge, Sn, Pb) and C2H2 have been calculated at the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVDZ level, and the nature of these complexes has been investigated by natural bond orbital. The four types (type-A, type-B, type-C and type-D) of complexes can be located for H2Si = TH2···C2H2 system. The complexes involving H2Si = TH2···C2F2 and H2Si = TH2···C2(CN)2 have also been examined to explore the substituent effects. Some complexes which are stable for H2Si = TH2···C2H2 system become unstable for H2Si = TH2···C2F2 or H2Si = TH2···C2(CN)2 system, while other complexes which are unstable for H2Si = TH2···C2H2 system become stable for H2Si = TH2···C2F2 or H2Si = TH2···C2(CN)2 system. [ABSTRACT FROM AUTHOR]

Transvaginal ultrasound (TVUS) and MRI are currently two mainstream imaging techniques used to diagnose deep endometriosis (DE) with comparable accuracy, but there is still ample room for improvement. As endometriotic lesions progress to fibrosis concomitant with the increase in tissue stiffness, transvaginal elastosonography (TVESG) is well-suited for diagnosing DE. To test the hypothesis that lesional stiffness as measured by TVESG correlates with the extent of lesional fibrosis, the markers of progression, hormonal receptor expression, and vascularity, we recruited 30 patients suspected to have DE who went through pelvic examination, TVUS and/or MRI, and TVESG and were ultimately diagnosed by histology. Their lesional tissue samples were subjected to immunohistochemistry analysis of markers for epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), estrogen and progesterone receptors (ERβ and PR), microvessel density (MVD), and vascularity, as well as quantification of lesional fibrosis. We found that pelvic examination, TVUS, and MRI detected 83.3%, 66.7%, and 83.3% of all DE cases, respectively, while TVESG detected them all. The lesions missed by pelvic exam, TVUS and MRI were significantly smaller than those detected but nonetheless had higher lesional stiffness. Lesional stiffness correlated closely and positively with the extent of lesional fibrosis, negatively with the markers of EMT, MVD, vascularity, and PR expression, but positively with the marker for FMT and ERβ. Thus, through the additional use of information on differential stiffness between DE lesions and their surrounding tissues, TVESG improves diagnostic accuracy, provides a ballpark estimate on the developmental stage of the lesions, and may help clinicians choose the best treatment modality. [ABSTRACT FROM AUTHOR]

In the information age, the amount of data is huge which shows an exponential growth. In addition, most services of application need to be interdependent with data, cause that they can be executed under the driven data. In fact, such a data-intensive service deployment requires a good coordination among different edge servers. It is not easy to handle such issues while data transmission and load balancing conditions change constantly between edge servers and data-intensive services. Based on the above description, this paper proposes a Data-intensive Service Edge deployment scheme based on Genetic Algorithm (DSEGA). Firstly, a data-intensive edge service composition and an edge server model will be generated based on a graph theory algorithm, then five algorithms of Genetic Algorithm (GA), Simulated Annealing Algorithm (SA), Ant Colony Algorithm (ACO), Optimized Ant Colony Algorithm (ACO_v) and Hill Climbing will be respectively used to obtain an optimal deployment scheme, so that the response time of the data-intensive edge service deployment reaches a minimum under storage constraints and load balancing conditions. The experimental results show that the DSEGA algorithm can get the shortest response time among the service, data components and edge servers. [ABSTRACT FROM AUTHOR]

The binary and ternary complexes composed of GeH3F, AsH2F and ring compounds (benzene, borazine and cyclopentadienyl anion) have been studied by theoretical calculations to understand the interplay between the tetrel bond and pnicogen bond interactions. The bonding strength of intermolecular interactions in these complexes is analyzed by means of atoms in molecules (AIM), natural bond orbital (NBO) and noncovalent interaction (NCI) index methods. The binary tetrel-bonded and pnicogen-bonded complexes can be classified as an n-type or π-type complex according to the orbital interactions involved in the complexes. Three binding modes can be distinguished according to the interplay between interactions for the ternary complexes. The binding mode A is characterized by the interplay between π-type tetrel bond and n-type pnicogen bond; binding mode B is characterized by the interplay between π-type pnicogen bond and n-type tetrel bond, and binding mode C is characterized by the interplay between π-type tetrel bond and π-type pnicogen bond. The binding modes A and B exhibit the synergistic interplay effect, while the antagonistic effect is reflected in mode C. The synergistic effect in binding modes A and B is stronger than antagonistic effect in mode C, and the synergistic effect in binding mode B is stronger than that in mode A. [ABSTRACT FROM AUTHOR]

[Display omitted] • The retention rate can be more helpful than MWCO for screening suitable membranes. • Ceramic NF membrane can maintain good stability during FOS purification. • Membranes with a high separation factor and low non-prebiotic rejection are better. High-purity fructooligosaccharides (FOS) with high economic value have been widely used in the food and medical fields. The use of ceramic nanofiltration (NF) membranes with narrow pore-size distributions have been proven to be a promising strategy for purifying FOS. The preliminary screening of membranes according to the retention rate of each membrane itself is more scientific than basing it only on the molecular weight cut-off. In addition, the yield, purity, membrane flux, and washing water volume of the product should be considered comprehensively. Here, the concentration of FOS feed should be controlled within 100 g·L−1, with the suggested settings for transmembrane pressure, cross-flow velocity, and operating temperature being 0.7 MPa, 1.2 m·s−1, and 60 °C, respectively. The model analysis showed that the NF membrane with a high separation factor and low non-prebiotic sugar rejection rate can obtain a high FOS yield and purity with less leachate addition. Moreover, the ceramic NF membrane can maintain a stable separation performance during the separation process, and the pure water flux can be recovered after cleaning, which has good application prospects in the FOS purification industry. [ABSTRACT FROM AUTHOR]

Biofilm growth on cohesive sediment deposits plays a crucial role in the inherent properties of aqueous environment, such as the biostabilization of sediment deposits, sediment-associated contaminant transport, and habitat change. Here, a specially designed cylinder was used for biofilm cultivation under static water (with sediment sizes of 0.02-0.05, 0.05-0.1, and 0.1-0.2 mm) and dynamic water flow conditions. A biomass dynamics model, including the accrual term and detachment term (velocity-dependent and/or autogenic), was proposed to study the effects of sediment size and hydrodynamic condition on biofilm growth. The results showed that more biofilm formed on fine sediment than coarse sediment due to the greater surface area for bacterial attachment and nutrients accumulation. Increased flow velocity inhibited biofilm accumulation and a greater velocity caused more velocity-dependent chronic detachment, resulting in less biofilm growth on sediment particles. Under static water condition, there was more biomass compared with dynamic water flow condition. The proposed model can reasonably reflect the evolution of biofilm growth, as well as the effects of sediment size and hydrodynamic condition, which might be applied for the management of natural aqueous systems. [ABSTRACT FROM AUTHOR]

The binding behavior of coinage metal anions with some electron-deficient arenes has been investigated by MP2 calculations, and the character of interactions in these complexes has been examined by NBO analysis. The results indicate that coinage metal anions can interact with electron-deficient arenes to form anion-π, strong σ-type and hydrogen-bonding complexes. The σ-type structure is the global minimum for triazine, trifluorotriazine, hexafluorobenzene and tricyanobenzene, and the hydrogen-bonding structure is the global minimum for trifluorobenzene. There exist some differences in the stability of anion-π complexes for coinage metal anions: the anion-π complexes of Au are minima expect for triazine complex; the anion-π complexes of Ag are minima expect for tricyanobenzene complex; and the anion-π complexes of Cu are not minima expect for trifluorobenzene complex. The binding strength of anion-π and hydrogen-bonding complexes for Au is larger than that for Ag and Cu, but the binding strength of σ complex displays a different sequence: Cu > Au > Ag. The binding behavior of coinage metal anions is more similar to that of F than that of Cl and Br. The relaxed potential energy surface scans for some selected systems have been performed to help understand the interactions between coinage metal anions with electron-deficient arenes. [ABSTRACT FROM AUTHOR]

Melanoma is the most common form of skin cancer. Given its high metastasis and high recurrence, its therapies are constantly updated. The study aims to prove the efficacy of sodium thiosulfate (STS), an antidote to cyanide or nitroprusside poisoning, in melanoma treatment. We tested the effect of STS by culturing melanoma cells (B16 and A375) in vitro and establishing melanoma mouse models in vivo. The proliferation and viability of melanoma cells were measured by the CCK-8 test, cell cycle assay, apoptosis analysis, wound healing assay, and transwell migration assay. The expression of apoptosis-related molecules, epithelial-mesenchymal transition (EMT)-associated molecules, and the Wnt/β-catenin signaling pathway-related molecules were determined by Western blotting and immunofluorescence. The high metastasis of melanoma is considered to be linked to the EMT process. The scratch assay using B16 and A375 cells also showed that STS could inhibit the EMT process of melanoma. We demonstrated that STS inhibited the proliferation, viability, and EMT process of melanoma by releasing H 2 S. STS-mediated weakening of cell migration was related to the inhibition of the Wnt/β-catenin signaling pathway. Mechanistically, we defined that STS inhibited the EMT process via the Wnt/β-catenin signaling pathway. These results suggest that the negative effect of STS on melanoma development is mediated by the reduction of EMT via the regulation of the Wnt/β-catenin signaling pathway, which provides a new clue to treating melanoma. • STS treatment can inhibit melanoma cell proliferation, viability, and EMT process. • STS inhibits melanoma development via releasing H 2 S. • STS inhibits the EMT process via downregulating the activity of the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

The ternary complexes X · 1 · YF ( 1 = triazine, X = Cl, Br and I, Y = H, Cl, Br, I, PH and AsH) have been investigated by MP2 calculations to understand the noncovalently electron-withdrawing effects on anion-arene interactions. The results indicate that in binary complexes ( 1 · X), both weak σ-type and anion-π complexes can be formed for Cl and Br, but only anion-π complex can be formed for I. Moreover, the hydrogen-bonding complex is the global minimum for all three halides in binary complexes. However, in ternary complexes, anion-π complex become unstable and only σ complex can retain in many cases for Cl and Br. Anion-π complex keeps stable only when YF = HF. In contrast with binary complexes, σ complex become the global minimum for Cl and Br in ternary complexes. These changes in binding mode and strength are consistent with the results of covalently electron-withdrawing effects. However, in contrast with the covalently electron-withdrawing substituents, Cl and Br can attack the aromatic carbon atom to form a strong σ complex when the noncovalently electron-withdrawing effect is induced by halogen bonding. The binding behavior for I is different from that for Cl and Br in two aspects. First, the anion-π complex for I can also keep stable when the noncovalent interaction is halogen bonding. Second, the anion-π complex for I is the global minimum when it can retain as a stable structure. [ABSTRACT FROM AUTHOR]

Theinteractions between halogen-substituted s-trazine(C3H2N3X) and halide anions(Y–) have been investigated at the MP2/aug-cc-pVDZ(aug-cc-pVDZ-PP) level. C3H2N3X caninteract with halide anions to form five types of complexes (C3H2N3X·Y–): astrong σ-type interaction complex, a weak σ-type interactioncomplex, an anion−π interaction complex, a hydrogen-bondingcomplex, and a halogen-bonding complex. The binding energies, structures,and bonding characteristics of these complexes have been discussed.The local details of potential energy surfaces around the bindingsites for some selected complexes have been depicted. The resultsindicate that the binding behavior of F–is quitedifferent from that of Cl–, Br–, and I–. The potential energy surface is separatedinto two parts, the HB-σ–π region and the XB region,by a relatively high energy barrier for complexes C3H2N3Cl·Cl–, C3H2N3Br·Cl–, and C3H2N3I·Cl–. The HB-σ–πregion is characterized by the flat potential energy surface, indicatingthat the binding strength is retained when the anion is held overthe HB-σ–π region. The XB region is characterizedby the steeper potential energy surface, indicating that the bindingstrength is more sensitive to the anion position in this region. Thebinding strength of the HB-σ–π region is strongerthan that of the XB region for C3H2N3Cl·Cl–and C3H2N3Br·Cl–, whereas the binding strengthof the XB region is stronger than that of the HB-σ–πregion for C3H2N3I·Cl–. [ABSTRACT FROM AUTHOR]

Abstract: Background: Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in TCM. Research has shown baishao to have positive pharmacological actions, including, particularly, anti-inflammatory properties. In this paper we studied the influence of baishao extract on cAMP-phosphodiesterase (PDE) activity and related anti-inflammatory action to identify new pharmacologic action for its clinically widespread use. Methods: PDE activity was calculated by cAMP change examined with HPLC, respiratory burst of neutrophils was detected with method of cytochrome C reduction, elastase release was indicated with the substrate reduction, rat arthritis model was caused by complete Freund''s adjuvant, mouse capillary permeability model was made by acetic acid, and chemical constituents of baishao extract was identified by HPLC, mass spectroscopy and NMR spectrum. Results: Baishao extract had significant inhibition on cAMP-PDE activity (p <0.01), had dose dependent restraint on neutrophils respiratory burst (p <0.001), had inhibition at low concentration and promotion at high concentration on elastase release (p <0.05), and had obvious restraint on local inflammation of animal model (p <0.01). Analysis of HPLC, mass spectroscopy and NMR spectrum showed baishao extract mainly had five components (identified as gallic acid, paeoniflorin sulfonate, albiflorin, paeoniflorin and benzoic acid), among which gallic acid had the largest inhibition on cAMP-PDE activity. Conclusion: The anti-inflammatory effects of baishao may be mediated, at least in part, through its gallic acid content, and this effect may be regulated in part by an inhibition on cAMP-PDE. [Copyright &y& Elsevier]

Ab initio multiconfigurational CASSCF/MP2 method with the 6‐31G* basis set has been employed in studying the photochemistry of bicyclo[4.1.0]hept‐2‐ene upon direct photolysis. Our calculations involve the ground state (S0) and excited states (S1, T1, and T2). The ground‐state reaction pathways corresponding to the formation of the six products derived from bicyclo[4.1.0]hept‐2‐ene via two important diradical intermediates (D1 and D2) were mapped. It was found that there are various crossing points (conical intersections and singlet–triplet crossings) in the regions near D1 and D2. These crossing points imply that direct photolysis can lead to two possible radiationless relaxation routes: (1) S1 → S0, (2) S1 → T2 → T1 → S0. Computation indicates that the second route is not a competitive path with the first route during direct photolysis. The first route is initiated by barrierless cyclopropane bond cleavage to form two singlet excited diradical intermediates, followed by efficient decay to the ground‐state surface via three S1/S0 conical intersections in the regions near the diradical intermediates. All six ground‐state products can be formed via the three conical intersections almost without barrier after the decays. The barriers separating the diradical minima on S1 from the S1/S0 conical intersections were found to be very small with respect to the vertical excitation energy, which can explain why the product distribution is independent of excitation wavelength. Triplet surfaces are not involved in the first route, which agrees with the fact that the product contribution was unchanged by the addition of naphthalene. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005 [ABSTRACT FROM AUTHOR]

The photochemical reaction channels of cyclobutanone have been studied at the CASSCF level with a 6-31G* basis set. Starting from the n-π* excited-state (S1) cyclobutanone, the three reactions can take place: decarbonylation (produce CO and cyclopropane or propylene), cycloelimination (produce ketene and ethylene), and ring expansion (produce oxacarbene). Our computation indicates that decarbonylation products CO and triplet trimethylene are formed on the triplet n-π* excited state (T1) in a stepwise way via a biradical intermediate after intersystem crossing (ISC) to T1 from S1. And, then, the triplet trimethylene undergoes a second ISC to the ground state (S0) to produce the singlet trimethylene from which cyclopropane can be produced rapidly only overcoming a 1 to 2-kcal/mol barrier while propylene can be formed as a secondary product. The cycloelimination products ketene and ethylene are formed on the S0 in a concerted mechanism after internal conversion (IC) to S0 from S1 via a biradical conical intersection. The reaction channels corresponding to ring expansion on the S0, T1, and S1 states have also been discussed, and the likeliest reaction path is that oxacarbene is formed on the ground state following S1/S0 internal conversion. The surface topology of cyclobutanone on the S1 surface is characterized by a transition state separating the minimum from the S1/S0 conical intersection, which is consistent with the previous computations and can explain the wavelength dependence of the fluorescence emission yield. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2004 [ABSTRACT FROM AUTHOR]

T reg plays a pivotal role in the suppression of Th2 cell and the maintenance of immune homeostasis. The precise molecular mechanism underlying the disruption of T reg suppression of Th2 cell and the promotion of Th2 type inflammation in allergic diseases remains elusive. This study aims to investigate the molecular mechanism underlying quantitative and functional changes of T reg in AD. The molecular mechanism was investigated using flow cytometry, mRNA sequencing, co-culture experiments, co-immunoprecipitation, chromatin immunoprecipitation, and bisulfite sequencing in vitro or in AD mice model and patients with AD. Increased proportion of T reg was detected in mild and moderate AD. Conversely, characteristic decrease in both the number and CTLA-4 expression of T reg was relevant to serum IL-4 level in severe AD patients, which was verified under a high concentration of IL-4 treatment in vitro. The underlying mechanism is that IL-4/pSTAT6 pathway recruits DNMT1 and HDAC2 to inhibit transcriptional regulation of Foxp3 and CTLA-4 loci. High level of IL-4 impaired the suppression of T reg against Th2 cell differentiation mediated by CTLA-4, and blockade of IL-4Rα signaling in T reg restored T reg number and suppression of Th2 cell in AD model mice and patients with AD. The number of T reg is relevant to stratification of severity and serum IL-4 level in patients with AD. Abnormal high level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of T reg. The reduced expression of CTLA-4 on T reg induced by IL-4 impairs suppression of Th2 cell differentiation. • The number of T reg is relevant to stratification of severity and serum IL-4 level in patients with AD. • High level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of T reg in severe AD. • IL-4-induced reduction in both number and CTLA-4 expression of T reg impaired CTLA-4-mediated suppression of Th2 cell. • Blockade of IL-4Rα signaling in T reg restores T reg expression and its suppression of Th2 type inflammation in severe AD. [ABSTRACT FROM AUTHOR]

Deep learning (DL) techniques have grown in leaps and bounds in both academia and industry over the past few years. Despite the growth of DL projects, there has been little study on how DL projects evolve, whether maintainers in this domain encounter a dramatic increase in workload and whether or not existing maintainers can guarantee the sustained development of projects. To address this gap, we perform an empirical study to investigate the sustainability of DL projects, understand maintainers' workloads and workloads growth in DL projects, and compare them with traditional open‐source software (OSS) projects. In this regard, we first investigate how DL projects grow, then, understand maintainers' workload in DL projects, and explore the workload growth of maintainers as DL projects evolve. After that, we mine the relationships between maintainers' activities and the sustainability of DL projects. Eventually, we compare it with traditional OSS projects. Our study unveils that although DL projects show increasing trends in most activities, maintainers' workloads present a decreasing trend. Meanwhile, the proportion of workload maintainers conducted in DL projects is significantly lower than in traditional OSS projects. Moreover, there are positive and moderate correlations between the sustainability of DL projects and the number of maintainers' releases, pushes, and merged pull requests. Our findings shed lights that help understand maintainers' workload and growth trends in DL and traditional OSS projects and also highlight actionable directions for organizations, maintainers, and researchers. [ABSTRACT FROM AUTHOR]

Purpose: Colorectal cancer (CRC) is the third most common cancer in the world. The purpose of this study was to investigate the role of TNNT2 in the proliferation, migration and invasion of CRC cells and its expression in CRC tissues to better understand the regulatory role of TNNT2 in CRC. Methods: Western blotting (WB) and qPCR were used to detect the expression of TNNT2 in colorectal cancer tissues and paracancerous tissues. CCK-8, colony formation, Transwell and other experiments were used to clarify the role of TNNT2 in the proliferation, migration and invasion of colorectal cancer cells. Changes in TNNT2, EGFR and HER2 mRNA transcription levels were detected by SYBR Real-Time PCR assay, and the effects of TNNT2 overexpression or knockdown on the expression of EGFR, HER2 and EMT-related proteins in CRC cells were determined by WB. TNNT2 and EGFR intreaction was carried out in HCT116 cells by coimmunoprecipitation experiments. Results: The protein and mRNA expression level of TNNT2 in CRC tissues were higher than those in paracancerous tissues. The CCK-8 results suggested that overexpression of TNNT2 significantly promoted the proliferation of HCT116 and RKO cells, and TNNT2 konckdown gets the opposite result; and the colony formation results were the same as tthose of CCK-8 assay. Transwell invasion and migration experiments showed that overexpression of TNNT2 promoted the migration and invasion of HCT116 and PKO cells, and TNNT2 konckdown suppressed the migration and invasion of the these cells. The SYBR Green I real-time PCR method revealed that them RNA levels of TNNT2, EGFR and HER2 in the TNNT2 overexpression group were higher than those in RKO cells. WB showed that overexpressing TNNT2 increased the expression of EGFR and HER2 in HCT16 and RKO cells,decreased the expression of EMT marker E-cadherin, and increased the expression of Vimentin and N-cadherin. Konckdown of TNNT2 decreased the expression of EGFR and HER2, increased the expression of E-cadherin, and decreased the expression of Vimentin and N-cadherin in HCT16 and RKO cells. The immunocoprecipitation experiment showed that there was an interaction between EGFR and TNNT2. Conclusion: TNNT2 can promote the proliferation, invasion and metastasis of colorectal cancer cells. There is an interaction between TNNT2 and EGFR protein. TNNT2 can upregulate EGFR and HER2-related proteins in colorectal cancer cells and promote the occurrence of EMT. Therefore, TNNT2 can promote the invasion and metastasis of CRC cells through the EGFR/HER2/EMT signal axis, suggesting that TNNT2 is a potential target of CRC treatment. [ABSTRACT FROM AUTHOR]

Waste heat recovery is a key problem to be solved for metallurgical slag. Furthermore, the heat source is a current bottleneck for sewage sludge gasification technology. At present, there is no complete process system for the thermochemical conversion of sludge driven by metallurgical slag waste heat. To recover the waste heat of slag, a granulation and waste heat recovery system using the sewage sludge gasification reaction is proposed in this paper. The sludge gasification kinetics were analyzed using thermogravimetry (TG). The active catalytic components in both Cu and Ni slag were determined using X-ray diffractometry (XRD) and X-ray photoelectron spectroscopy (XPS). The results show that the metallurgical slag could improve the decomposition rate of the sludge gasification reaction. The main catalytic components were Fe3O4 and CaO for Cu slag and Ni slag, respectively. The conversion ratio was increased by 7.8% and 11.8%, while the activation energy decreased from 21.09 kJ/mol to 17.36 kJ/mol and 17.30 kJ/mol, respectively, when Cu slag and Ni slag were added. After oxidative modification, the catalytic function was enhanced for Cu slag, whereas it was weakened for Ni slag. [ABSTRACT FROM AUTHOR]

This meta-analysis was conducted to analyze the effect of NQO1 polymorphism on the warfarin maintenance dosage. Using strict inclusion and exclusion criteria, we searched PubMed, EMBASE, and the Cochrane Library for eligible studies published prior to July 7, 2021. The required data were extracted, and experts were consulted when necessary. Review Manager Version 5.4 software was used to analyze the relationship between NQO1 polymorphisms and the warfarin maintenance dosage. Four articles involving 757 patients were included in the meta-analysis. Patients who were NQO1 rs10517 G carriers (AG carriers or GG carriers) required a 48% higher warfarin maintenance dose than those who were AA carriers. Patients with NQO1 rs1800566 CT carriers required a 13% higher warfarin dose than those who were CC carriers, with no associations observed with the other comparisons of the NQO1 rs1800566 genotypes. However, the results obtained by comparing the NQO1 rs1800566 genotypes require confirmation, as significant changes in the results were found in sensitivity analyses. Our meta-analysis suggests that the NQO1 rs10517and NQO1 rs1800566 variant statuses affect the required warfarin maintenance dose. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Cardiac Troponin T (TNNT2) plays a potential oncogenic role in colorectal carcinogenesis" published in Cancer Cell International. The correction states that the order of the authors in the author list was incorrect, with the co-authors Yibing Liu and Zhiguo Zhou being transposed. The original article has been corrected. The publisher, Springer Nature, remains neutral regarding jurisdictional claims and institutional affiliations. The authors of the article are Yifan Liu, Ze Meng, Junqiang Niu, Le Tian, Yishan Chen, Qingju Meng, Yibing Liu, and Zhiguo Zhou. [Extracted from the article]

Mesenchymal stem cells (MSCs) are an important cell source for tissue homeostasis and repair due to their stemness characteristic. Lots of intrinsic signaling pathways have been reported to regulate MSC stemness, but the extrinsic signals such as sodium lactate, particularly in physiological conditions, are poorly understood. Herein, we evaluated the effect of sodium lactate on human MSC stemness regulation by examining colony-forming ability, energy metabolism, multi-lineage differentiation ability, and pluripotent gene and protein expression. The underlying mechanism was further investigated with gene knockdown as well as small molecule interference and rescue experiments. We found that: (1) low concentration (1 mM) of sodium lactate promoted the stemness of human MSCs; (2) the upregulation of glycolysis was responsible for the MSC stemness promotion; (3) lysine demethylase 6B (KDM6B) was the key regulator which mediated sodium lactate-induced glycolysis and human MSC stemness enhancement. This study indicated that sodium lactate played an important role in human MSC stemness maintenance in physiological conditions, which could be related to KDM6B mediated metabolic regulation. It would provide new insight into stem cell biology, and contribute to cell transplantation and tissue regeneration strategies. • Low concentration (1 mM) of sodium lactate promoted the stemness of human mesenchymal stem cells (MSCs). • The upregulation of glycolysis was responsible for the MSC stemness promotion. • Lysine demethylase 6B (KDM6B) was the key regulator of the sodium lactate-induced glycolysis and MSC stemness enhancement. [ABSTRACT FROM AUTHOR]

Abstract Nanoparticles are widely developed and utilized in the pharmaceutical and medicine industry, as they can be easily distributed and infiltrated throughout the whole body once administered; however, the body wide effect of nanoparticles infiltration is still unclear. In this study, we developed a new strategy of Nano Genome Altas (NGA) of multi-tissues to study the acute Body-wide-Organ-Transcriptomic response to nanomaterials. Hydroxyapatite(HA)-Nanoparticles (HANPs) was applied in this study as an example both in vitro and in vivo. Results showed that the effect of HANPs is organ specific and mainly related to immune responses in spleen and muscle, proliferation in spleen and bone, stress and apoptosis in spleen and PBMC, ion transport in spleen, kidney, and liver tissues, metabolism in heart, spleen, and muscle, as well as tissue specific epigenetic and signal pathways. In vitro experiments also confirmed that the effects of HANPs on different tissue stem cells were tissue specific. Thus, Nano Genome Altas can provide a body-wide view of the transcriptomic response of multiple organs and tissue specific stem cells to HANPs; it could also be useful for optimizing HANPs and other nano-delivery systems. [ABSTRACT FROM AUTHOR]

Although some local governments in China have implemented mandatory environmental regulation policies to address severe pollution problems due to expanding pig production, whether such executive policies conform to the objective development law of pig production and are capable of effectively reducing pollution emissions is a pending issue. In this paper, we establish a theoretical model to illuminate the potential effects of the scale and agglomeration of pig production on the pollutant treatment rate and propose four theoretical hypotheses. Furthermore, we use survey data collected from Jiaxing city – the largest pig supply base in China's Yangtze River Delta region – and employ both linear and nonlinear models to empirically test the theoretical hypotheses. The results show that the rate of faeces applied to the fields as manure decreases with the scale of pig production, while the rate of other harmless modes of pollutant treatment increases with the scale of production, resulting in a U-shaped relationship between the pollutant treatment rate and the scale of pig production. In addition, the total pollutant treatment rate increases with the agglomeration of pig production. We suggest that effective environmental regulation of pig production should differentiate between the types of pollution emissions generated by pig producers; according to their scale of production, pig producers should be classified as point or nonpoint sources of pollution. [ABSTRACT FROM AUTHOR]

The mobility of phosphorus (P) induced by sediment resuspension have been examined in a circulated flume. During the flume run, the water level and velocity were monitored, and water samples were taken for measurement of sediment and P concentrations. Peak values of both the P and sediment concentrations existed at x = 4 m, and then decreased slightly along the flume due to deposition. A faster P release was observed for coarser sediment, while a more sustained P release for finer sediment. Combining with the measured data from Yangtze River and sorption experiment, the relation between the load of total P ( L TP ) and sediment load ( Q s ) was estimated, and the expressions of distribution coefficient K d and the concentration of particulate P (PP) were obtained. This study established a bridge between the small-scale sorption experiment and the field observation of natural scale, providing references for the management of contaminated sediment in natural rivers. [ABSTRACT FROM AUTHOR]

Objective Chondrocyte hypertrophy and mineralization are considered to be important pathologic factors in osteoarthritis (OA). We previously reported that Rac1 was aberrantly activated to promote chondrocyte hypertrophy, mineralization, and expression of matrix metalloproteinase 13 and ADAMTS in OA. However, the underlying mechanism of aberrant Rac1 activation in OA is unclear. The present study was undertaken to identify the specific molecular regulator controlling Rac1 activity in OA, as well as to investigate its function in chondrocyte hypertrophy, mineralization, and OA development. Methods Expression levels of 28 upstream regulators of Rac1 activity, including 8 GTPase-activating proteins (GAPs) and 20 guanine nucleotide exchange factors, in OA and normal cartilage were assessed by quantitative polymerase chain reaction. Chondrocytes were transduced with lentiviral vectors encoding OCRL1, GAP, non-GAP, CA-Rac1, and DN-Rac1, either alone or in combination. Alkaline phosphatase staining was used as a marker of chondrocyte hypertrophy. Rac1 activity was analyzed by pulldown assay. Finally, OA was established in mice by surgical transection of the anterior cruciate ligament and cutting of the medial meniscus. The mice were injected intraarticularly with OCRL1-encoding lentivirus, and whole joints were assessed histologically 6 weeks after surgery. Results OCRL1 was abundantly expressed in normal cartilage and was the only significantly down-regulated RacGAP in OA cartilage. Overexpression of OCRL1 inhibited interleukin-1β-induced Rac1 activity, chondrocyte hypertrophy, and expression of hypertrophy-related genes. Conversely, knockdown of OCRL1 elevated Rac1 activity and promoted chondrocyte hypertrophy and mineralization. Further, OCRL1 modulated Rac1 activity via its GAP domain. Finally, intraarticular injection of OCRL1-encoding lentivirus protected against destruction and degeneration of cartilage in the mouse OA model. Conclusion OCRL1 acts as a RacGAP in cartilage to impede chondrocyte hypertrophy and OA development through modulating Rac1 activity. This regulatory pathway might provide potential targets for the development of new therapies for OA. [ABSTRACT FROM AUTHOR]

Abstract: This work aims to develop curcumin (Cur) loaded biodegradable self-assembled polymeric micelles (Cur-M) to overcome poor water solubility of Cur and to meet the requirement of intravenous administration. Cur-M were prepared by solid dispersion method, which was simple and easy to scale up. Cur-M had a small particle size of 28.2±1.8nm and polydisperse index (PDI) of 0.136±0.050, and drug loading and encapsulation efficiency of Cur-M were 14.84±0.11% and 98.91±0.70%, respectively. Besides, in vitro release profile showed a significant difference between rapid release of free Cur and much slower and sustained release of Cur-M. Cytotoxicity study showed that the encapsulated Cur remained its potent anti-tumor effect. Furthermore, Cur-M were more effective in inhibiting tumor growth and spontaneous pulmonary metastasis in subcutaneous 4T1 breast tumor model, and prolonged survival of tumor-bearing mice. In addition, immunofluorescent and immunohistochemical studies also showed that tumors of Cur-M-treated mice had more apoptosis cells, fewer microvessels, and fewer proliferation-positive cells. In conclusion, polymeric micelles encapsulating Cur were developed with enhanced anti-tumor and anti-metastasis activity on breast tumor, and Cur-M is excellent water-based formulation of Cur which may serve as a candidate for breast cancer therapy. [Copyright &y& Elsevier]

Abstract: For developing aqueous formulation and improving anti-tumor activity of curcumin (Cur), we prepared Cur encapsulated MPEG-PCL micelles by solid dispersion method without using any surfactants or toxic organic solvent. Cur micelles could be lyophilized into powder form without any cryoprotector or excipient, and the re-dissolved Cur micelles are homogenous and stable. Molecular modeling study suggested that Cur tended to interact with PCL serving as a core embraced by PEG as a shell. After Cur was encapsulated into polymeric micelles, cytotoxicity and cellular uptake were both increased. Cur micelles had a stronger inhibitory effect on proliferation, migration, invasion, and tube formation of HUVECs than free Cur. Besides, Cur micelles showed a sustained in vitro release behavior and slow extravasation from blood vessels in transgenic zebrafish model. Embryonic angiogenesis and tumor-induced angiogenesis were both dramatically inhibited by Cur micelles in transgenic zebrafish model. Furthermore, Cur micelles were more effective in inhibiting tumor growth and prolonged survival in both subcutaneous and pulmonary metastatic LL/2 tumor models. In pharmacokinetic and tissue distribution studies, Cur micelles showed higher concentration and longer retention time in plasma and tumors. Our findings suggested that Cur micelles may have promising applications in pulmonary carcinoma therapy. [Copyright &y& Elsevier]

Changes in the stiffness of chondrocyte extracellular matrix (ECM) are involved in the pathological progression of osteoarthritis (OA). However, the downstream responses of cartilage ECM stiffness are still unclear. YAP (Yes-associated protein) has been extensively studied as a mechanotransducer, we thus hypothesized that by targeting the downstream molecule activity of ECM stiffness could maintain chondrocyte phenotype and prevent cartilage degeneration in OA. Here, we showed that human cartilage matrix stiffened during pathological progression of OA, and the chondrocyte YAP activity was associated with ECM stiffness. We then mimicked the physiological and pathological stiffness of human cartilage by using PDMS-based substrates, and found that YAP was activated in chondrocytes seeded on stiff substrate, gradually losing their phenotype. In addition, it was observed that YAP was also significantly activated in mice OA development, and conditional knockout (cKO) of YAP in mice preserved collagen II expression and protected cartilage from degeneration in the OA model. Furthermore, intra-articular injection of YAP-selective inhibitor, Verteporfin, significantly maintained cartilage homeostasis in mice OA model. This study indicates that the application of mechanotransducer-targeted drugs could be a potential therapeutic approach for cartilage repair in OA. [ABSTRACT FROM AUTHOR]