Effects of Salmonella Outer Membrane Vesicles on Intestinal Microbiota and Intestinal Barrier Function.

Salmonella enterica is one of the most important zoonotic pathogens causing foodborne gastroenteritis worldwide. Outer membrane vesicles (OMVs) are lipid-bilayer vesicles produced by Gram-negative bacteria, which contain biologically active components. We hypothesized that OMVs are an important weapon of S. enterica to initiate enteric diseases pathologies. In this study, the effects of S. enterica OMVs (SeOMVs) on intestinal microbiota and intestinal barrier function were investigated. In vitro fecal culture experiments showed that alpha diversity indexes and microbiota composition were altered by SeOMV supplementation. SeOMV supplementation showed an increase of pH, a decrease of OD630 and total short chain fatty acid (SCFA) concentrations. In vitro IPEC-J2 cells culture experiments showed that SeOMV supplementation did not affect the IPEC-J2 cell viability and the indicated genes expression. In vivo experiments in mice showed that SeOMVs had adverse effects on average daily gain (p < 0.05) and feed:gain ratio (p < 0.05), and had a tendency to decrease the final body weight (p = 0.073) in mice. SeOMV administration decreased serum interleukin-10 level (p < 0.05), decreased the relative abundance of bacteria belonging to the genera BacC-u-018 and Akkermansia (p < 0.05). Furthermore, SeOMV administration damaged the ileum mucosa (p < 0.05). These findings suggest that SeOMVs play an important role in the activation of intestinal inflammatory response induced by S. enterica, and downregulation of SCFA-producing bacteria is a possible mechanism.

Nickel-Catalyzed Reductive Dicarbofunctionalizations of Alkenes for the Synthesis of Difluorocarbonyl Oxindoles and Isoquinoline-1,3-diones.

A novel and efficient strategy for the construction of difluorocarbonyl-oxindole and difluorocarbonyl-isoquinoline-1,3-dione derivatives involving nickel-catalyzed intramolecular Heck-type cyclizations followed by intermolecular cross-couplings has been developed. This approach features high functional group tolerance, broad substrate scope, and operational simplicity under mild conditions, thus providing a new method for the rapid difluorocarbonyl-functionalization of alkenes to construct the structurally diversified five- and six-membered heterocycles.

Nanoaggregates of Disulfide-Decorated TrxR Inhibitor Promote Cellular Uptake, Selective Targeting, and Antitumor Efficacy.

Three self-assembled nanoaggregates (CPUL1-LA NAs, CPUL1-DA NAs, and CPUL1-AA NAs) were constructed through lipoic acid (LA), dithiodipropionic acid (DA), and adipic acid (AA) decorated TrxR inhibitor (CPUL1), respectively. Measurements of DLS, TEM, UV-vis, fluorescence, 1H NMR, ITC, and MTT assays verified disulfide-containing CPUL1-LA NAs and CPUL1-DA NAs spontaneously assembled carrier-free nanoparticles in aqueous solution, which possessed high drug contents, excellent stability, improved cytotoxicity against HUH7 hepatoma cells, and potential biosafety because of low cytotoxicity against L02 normal cells. In contrast, disulfide-free CPUL1-AA NAs happened to aggregate and precipitate after 48 h, which showed distinct instability in aqueous solution. Thus, disulfide units seemed to be crucial for constructing controllable and stable nanoaggregates. While measuring the reduction of nanoaggregates by TrxR/NADPH and GSH/GR/NADPH, cyclic disulfide of LA and linear disulfide of DA were verified to endow the nanoaggregates with targeting ability to respond specifically to TrxR over GSH. Furthermore, by tests of flow cytometry, fluorescence images, and CLSM, both CPUL1-LA NAs and CPUL1-DA NAs displayed a faster cellular uptake characteristic to be internalized by cancer cells and could generate more abundant ROS to induce cell apoptosis than that of free CPUL1, resulting in significantly improved antitumor efficacy against HUH7 cells in vitro.

Design, synthesis and biological evaluations of diverse Michael acceptor-based phenazine hybrid molecules as TrxR1 inhibitors.

A series of novel phenazine derivatives (1~27) containing the Michael acceptor scaffolds were designed and synthesized in this study. Some compounds exhibited selective cytotoxicity against Bel-7402 cancer cell line in vitro, in which compound 26 were found to have the best antiproliferative activity. Meanwhile, compound 26 showed no obvious cell toxicity against human normal liver epithelial L02 cells, which means this compound possessed a better safety potential. In the following research, compound 26 was verified to inhibit TrxR1 enzyme activity, ultimately resulting in cellular molecular mechanism events of apoptosis including growth of intracellular ROS level, depletion of reduced Trx1, liberation of ASK1 and up-regulation of p38, respectively. Together, all these evidences implicated that compound 26 acted as the TrxR1 inhibitor against Bel-7402 cells, and could activate apoptosis through the ROS-Trx-ASK1-p38 pathway.

Recent Advances of Polycationic siRNA Vectors for Cancer Therapy.

Small interfering RNAs (siRNAs) have recently emerged as a new class of biopharmaceuticals for the treatment of various diseases, including genetic diseases, viral infections, heritable disorders, and most prominently, cancer. However, clinical applications of siRNA-based therapeutics through intravenous administration have been limited due to their rapid degradation and renal clearance, poor cellular uptake, low cytoplasmic release by escaping endocytic uptake, and off-target effects. The success of siRNA-based therapeutics depends upon the design and creation of efficient delivery vectors that should be able to protect siRNA from in vivo degradation and specifically deliver siRNA to cytosol of target cells. Over the past decade, myriad types of carrier systems composed of cationic polymers have been designed for delivery of siRNA to tumor cells. In this review, we overview recent advances in siRNA delivery by using these promising nonviral carrier systems in diverse approaches to overcome the delivery hindrances and provide valuable understanding to direct the future design of siRNA delivery carriers.

Tumor-Adhesive and pH-Degradable Microgels by Microfluidics and Photo-Cross-Linking for Efficient Antiangiogenesis and Enhanced Cancer Chemotherapy.

Tumor angiogenesis with the vascular network formation provides nutrition and oxygen for cancer cells, promoting the proliferation and metastasis of malignant tumors. Bevacizumab (Bev) as an efficient antiangiogenic antibody is able to normalize the tumor vasculature with better blood flow and reduced interstitial fluid pressure, allowing drugs with more uniform distribution and deeper penetration into the tumor; however, it is highly difficult to realize the simultaneous delivery of Bev and anticancer drugs localized at the tumor tissue. Here, we prepared tumor-adhesive and pH-degradable poly(vinyl alcohol) (PVA) microgels for tumor-localized delivery of Bev and docetaxel (DTX), to achieve efficient antiangiogenesis and enhanced cancer chemotherapy. PVA microgels (∼200 µm) decorated with tissue-adhesive dopamine (DA) moieties were fabricated by a combination of high-throughput microfluidics technology and photo-cross-linking chemistry with a considerable coencapsulation efficiency for Bev and DTX. PVA microgels exhibited sustained drug release at the tumoral acidic conditions as the microgel degradation, and DA moieties on the microgels facilitated Bev with long retention at the tumor tissue, highly blocking the vascular endothelial growth factor (VEGF) and inhibiting tumor angiogenesis, as compared to free Bev or no DA-decorated microgels. In addition, the antitumor activity on the 4T1-Luc breast tumor mouse model treated with Bev/DTX-coloaded microgels showed obviously superior tumor growth inhibition than the other treatment groups, in which the combinational therapy efficacy of Bev and DTX mediated by the tumor-adhesive microgels was further confirmed by the immunohistochemistry (IHC) analysis. These PVA microgels with efficient antiangiogenesis and enhanced cancer chemotherapy provide a highly potential platform to treat different malignant tumors as well as the recurrent and metastatic tumors.

Identification of ortho-naphthoquinones as anti-AML agents by highly efficient oxidation of phenols.

A straightforward method for synthesizing ortho-naphthoquinones was identified using an easily available cobalt-Schiff base complex. Efficient oxidation of phenols to ortho-naphthoquinones was useful in obtaining compounds with potent biological activity for the treatment of acute myeloid leukemia (AML). Among these compounds, the compound 4h effectively inhibited the proliferation of different AML cell lines in vitro. Further in vivo antitumor studies indicated that 4h at 40 mg/kg/d led to tumor regression in led to tumor regression in an MV4-11 xenograft model without evident toxicity. The cobalt-Schiff base complex was found to be an efficient catalyst in the transformation of phenols to ortho-quinones, and the compound 4h represents a potential scaffold to optimize the production of a treatment for AML.

Immunomodulatory activities of proteins from Astragalus membranaceus waste.

BACKGROUND: Astragalus membranaceus is a traditional Chinese medicine that has a long history of medical applications. It is of interest to investigate the functional components of A. membranaceus waste with regard to its development and utilization and increasing resource utilization. RESULTS: The protein AMWP was isolated from the A. membranaceus waste. This protein was further purified by DEAE-cellulose-52 chromatography and Sephadex G-200 size-exclusion chromatography to obtain three fractions, named AMWPDG2, AMWPDG4 and AMWPDG6. Then, their immunomodulatory activities were evaluated by using cell model experiments. The results indicated that the protein fractions could significantly increase the proliferation of splenic lymphocytes, peritoneal macrophages and bone-marrow-derived cells (BMDCs). AMWPDG2 showed the highest immunocompetence. AMWPDG2, AMWPDG4 and AMWPDG6 not only significantly improved the phagocytosis and immunomodulatory factors (interleukin (IL)-6, tumor necrosis factor-α, nitric oxide, hydrogen peroxide) secretion of peritoneal macrophages, but also promoted the expression of inflammatory cytokines (IL-6, IL-12 p40, IL-1ß, IL-1α) and chemokines (CXCL1, CCL3) in BMDCs. CONCLUSION: Taken together, these results indicated that three protein fractions from the A. membranaceus waste might be a potential natural immunomodulator. Moreover, it also provided the theoretical basis for further researching the mechanism of AMWPDG2, AMWPDG4 and AMWPDG6 on improving the immune response. © 2019 Society of Chemical Industry.

Promoted Chondrogenesis of Cocultured Chondrocytes and Mesenchymal Stem Cells under Hypoxia Using In-situ Forming Degradable Hydrogel Scaffolds.

We investigated the effects of different oxygen tension (21% and 2.5% O2) on the chondrogenesis of different cell systems cultured in pH-degradable PVA hydrogels, including human articular chondrocytes (hACs), human mesenchymal stem cells (hMSCs), and their cocultures with a hAC/hMSC ratio of 20/80. These hydrogels were prepared with vinyl ether acrylate-functionalized PVA (PVA-VEA) and thiolated PVA-VEA (PVA-VEA-SH) via Michael-type addition reaction. The rheology tests determined the gelation of the hydrogels was controlled within 2-7 min, dependent on the polymer concentrations. The different cell systems were cultured in the hydrogel scaffolds for 5 weeks, and the safranin O and GAG assay showed that hypoxia (2.5% O2) greatly promoted the cartilage matrix production with an order of hAC > hAC/hMSC > hMSC. The real time quantitative PCR (RT-PCR) revealed that the hMSC group exhibited the highest hypertrophic marker gene expression (COL10A1, ALPL, MMP13) as well as the dedifferentiated marker gene expression (COL1A1) under normoxia conditions (21% O2), while these expressions were greatly inhibited by coculturing with a 20% amount of hACs and significantly further repressed under hypoxia conditions, which was comparative to the sole hAC group. The enzyme-linked immunosorbent assay (ELISA) also showed that coculture of hMSC/hAC greatly reduced the catabolic gene expression of MMP1 and MMP3 compared with the hMSC group. It is obvious that the hypoxia conditions promoted the chondrogenesis of hMSC by adding a small amount of hACs, and also effectively inhibited their hypotrophy. We are convinced that coculture of hAC/hMSC using in situ forming hydrogel scaffolds is a promising approach to producing cell source for cartilage engineering without the huge needs of primary chondrocyte harvest and expansion.

[Preparation of curcumin-EC sustained-release composite particles by supercritical CO2 anti-solvent technology].

Curcumin-ethyl-cellulose (EC) sustained-release composite particles were prepared by using supercritical CO2 anti-solvent technology. With drug loading and yield of inclusion complex as evaluation indexes, on the basis of single factor tests, orthogonal experimental design was used to optimize the preparation process of curcumin-EC sustained-release composite particles. The experiments such as drug loading, yield, particle size distribution, electron microscope analysis (SEM) , infrared spectrum (IR), differential scanning calorimetry (DSC) and in vitro dissolution were used to analyze the optimal process combination. The orthogonal experimental optimization process conditions were set as follows: crystallization temperature 45 degrees C, crystallization pressure 10 MPa, curcumin concentration 8 g x L(-1), solvent flow rate 0.9 mL x min(-1), and CO2 velocity 4 L x min(-1). Under the optimal conditions, the average drug loading and yield of curcumin-EC sustained-release composite particles were 33.01% and 83.97%, and the average particle size of the particles was 20.632 µm. IR and DSC analysis showed that curcumin might complex with EC. The experiments of in vitro dissolution showed that curcumin-EC composite particles had good sustained-release effect. Curcumin-EC sustained-release composite particles can be prepared by supercritical CO2 anti-solvent technology.

Dually crosslinked degradable polyionic micelles for sustained glucose-responsive insulin release.

Glucose -sensitive delivery systems hold great promise as a therapeutic approach for high-incidence diabetes owing to their ability to release insulin whenever elevated glycemia is detected. However, they are unstable in a hyperglycemic environment, which leads to short-term sustained insulin release. Herein, we designed dually crosslinked insulin polyionic micelles (DCM@insulin) based on triblock polymers of o-glycol and phenylboronic acid-functionalized poly(ethylene glycol)-poly(dimethylamino carbonate)-poly(dimethylamino-trimethylene carbonate) (mPEG-P(AC-co-MPD)-PDMAC and mPEG-P(AC-co-MAPBA)-PDMATC, respectively) for sustained glucose-responsive insulin release. DCM@insulin with a phenylboronic acid ester structure (first crosslinking structure) enhanced glycemic responsiveness by regulating insulin release in a hyperglycemic environment. Additionally, the UV-crosslinking structure (second crosslinking structure) formed by the residual double bonds in AC units endowed DCM@insulin with the ability to effectively protect the loaded insulin against protease degradation and avoid burst release under multiple insulin release. The in vivo findings demonstrated that DCM@insulin effectively maintained glycemic levels (BGLs) within the normal range for 6 h in comparison to single-crosslinked micelles (SCM@insulin). Therefore, the glucose-responsive and dually crosslinked polyionic micelle system exhibits potential as a viable option for the treatment of diabetes.

Size-tailored and acid-degradable polyvinyl alcohol microgels for inhalation therapy of bacterial pneumonia.

Administration of antibiotics via inhalation is considered an effective strategy for pneumonia treatment; however, it encounters challenges related to the development of drug formulations with precise particle sizes and controlled release profiles. Herein, size-tailored and acid-degradable polyvinyl alcohol (PVA) microgels are utilized for nebulized inhalation delivery of piperacillin (PIP) antibiotics to effectively treat pneumonia. These microgels loaded with PIP (G@PIP) were prepared through the UV-crosslinking of thermo-triggered vinyl ether methacrylate-functionalized PVA (PVAVEMA) micro-aggregates in aqueous solution. The size of G@PIP microgels could be tailored by adjusting concentrations during the crosslinking process above phase-transition temperature at 15 °C. Additionally, under simulated inflammatory acidic conditions, the G@PIP microgels degraded and released PIP with relatively high inhibition efficiency against E. coli. Furthermore, in vivo therapeutic outcomes revealed that inhalational delivery of G@PIP microgel with a medium-size of 3.5 µm (G-3.5@PIP) exhibited superior lung deposition compared to other microgel sizes owing to its reduced exhalation and enhanced diffusion capacity within the pulmonary system. The high accumulation of G-3.5@PIP significantly reduced E. coli infection and associated inflammation while maintaining the biocompatibility of the microgels. Overall, these acid-degradable PVA microgels offer a versatile and efficacious inhalation therapy for pneumonia-associated infections.

PVA-based bulk microneedles capable of high insulin loading and pH-triggered degradation for multi-responsive and sustained hypoglycemic therapy.

"Closed-loop" insulin-loaded microneedle patche shows great promise for improving therapeutic outcomes and life quality for diabetes patients. However, it is typically hampered by limited insulin loading capacity, random degradation, and intricate preparation procedures for the independence of the "closed-loop" bulk microneedles. In this study, we combined the solubility of microneedles and "closed-loop" systems and designed poly(vinyl alcohol)-based bulk microneedles (MNs@GI) through in situ photopolymerization for multi-responsive and sustained hypoglycemic therapy, which significantly simplified the preparation process and improved insulin loading. GOx/insulin co-encapsulated MNs@GI with a phenylboronic ester structure improved glycemic responsiveness to control the insulin release under high glucose conditions and reduced inflammation risk in the normal skin. MNs@GI could further degrade to increase insulin release due to the crosslinked acetal-linkage hydrolysis in the presence of gluconic acid, which was caused by GOx-mediated glucose-oxidation in a hyperglycemic environment. The in vivo results showed that MNs@GI effectively regulated glycemic levels within the normal range for approximately 10 h compared to that of only insulin-loaded microneedles (MNs@INS). Consequently, the highly insulin-loaded, multi-responsive, and pH-triggered MN system has tremendous potential for diabetes treatment.

Photothermal-controlled NO-releasing Nanogels reverse epithelial-mesenchymal transition and restore immune surveillance against cancer metastasis.

Metastasis leads to high mortality among cancer patients. It is a complex, multi-step biological process that involves the dissemination of cancer cells from the primary tumor and their systemic spread throughout the body, primarily through the epithelial-mesenchymal transition (EMT) program and immune evasion mechanisms. It presents a challenge in how to comprehensively treat metastatic cancer cells throughout the entire stage of the metastatic cascade using a simple system. Here, we fabricate a nanogel (HNO-NG) by covalently crosslinking a macromolecular nitric oxide (NO) donor with a photothermal IR780 iodide-containing hyaluronic acid derivative via a click reaction. This enables stable storage and tumor-targeted, photothermia-triggered release of NO to combat tumor metastasis throughout all stages. Upon laser irradiation (HNO-NG+L), the surge in NO production within tumor cells impairs the NF-κB/Snail/RKIP signaling loop that promotes the EMT program through S-nitrosylation, thus inhibiting cell dissemination from the primary tumor. On the other hand, it induces immunogenic cell death (ICD) and thereby augments anti-tumor immunity, which is crucial for killing both the primary tumor and systemically distributed tumor cells. Therefore, HNO-NG+L, by fully leveraging EMT reversal, ICD induction, and the lethal effect of NO, achieved impressive eradication of the primary tumor and significant prevention of lung metastasis in a mouse model of orthotropic 4T1 breast tumor that spontaneously metastasizes to the lungs, extending the NO-based therapeutic approach against tumor metastasis.

ROS-responsive core-shell nano-inhibitor impedes pyruvate metabolism for reinforced photodynamic therapy and interrupted pre-metastatic niche formation.

The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core-shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. STATEMENT OF SIGNIFICANCE: In the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core-shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.

Ursodeoxycholic Acid-Decorated Zwitterionic Nanoparticles for Orally Liver-Targeted Close-Looped Insulin Delivery.

Oral insulin therapies targeting the liver and further simulating close-looped secretion face significant challenges due to multiple trans-epithelial barriers. Herein, ursodeoxycholic acid (UDCA)-decorated zwitterionic nanoparticles (NPs) (UC-CMs@ins) are designed to overcome these barriers, target the liver, and respond to glycemia, thereby achieving oral one-time-per-day therapy. UC-CMs@ins show excellent mucus permeability through the introduction of zwitterion (carboxy betaine, CB). Furthermore, UC-CMs@ins possess superior cellular internalization via proton-assisted amino acid transporter 1 (PAT1, CB-receptor) and apical sodium-dependent bile acid transporter (ASBT, UDCA-receptor) pathways. Moreover, UC-CMs@ins exhibit excellent endolysosomal escape ability and improve the basolateral release of insulin into the bloodstream via the ileal bile acid-binding protein and the heteromeric organic solute transporter (OSTα- OSTß) routes compared with non-UDCA-decorated C-CMs@ins. Therefore, CB and UDCA jointly overcome mucus and intestinal barriers. Additionally, UC-CMs@ins prevent insulin degradation in the gastrointestinal tract for crosslinked structure, improve insulin accumulation in the liver for UDCA introduction, and effectively regulate glycemia for "closed-loop" glucose control. Surprisingly, oral ingestion of UC-CMs@ins shows a superior effect on glycemia (≈22 h, normoglycemia) and improves postprandial glycemic levels in diabetic mice, illustrating the enormous potential of the prepared NPs as a platform for oral insulin administration in diabetes treatment.

Cascade-Catalyzed Nanogel for Amplifying Starvation Therapy by Nitric Oxide-Mediated Hypoxia Alleviation.

Glucose oxidase (Gox)-mediated starvation therapy offers a prospective advantage for malignancy treatment by interrupting the glucose supply to neoplastic cells. However, the negative charge of the Gox surface hinders its enrichment in tumor tissues. Furthermore, Gox-mediated starvation therapy infiltrates large amounts of hydrogen peroxide (H2O2) to surround normal tissues and exacerbate intracellular hypoxia. In this study, a cascade-catalyzed nanogel (A-NE) was developed to boost the antitumor effects of starvation therapy by glucose consumption and cascade reactive release of nitric oxide (NO) to relieve hypoxia. First, the surface cross-linking structure of A-NE can serve as a bioimmobilization for Gox, ensuring Gox stability while improving the encapsulation efficiency. Then, Gox-mediated starvation therapy efficiently inhibited the proliferation of tumor cells while generating large amounts of H2O2. In addition, covalent l-arginine (l-Arg) in A-NE consumed H2O2 derived from glucose decomposition to generate NO, which augmented starvation therapy on metastatic tumors by alleviating tumor hypoxia. Eventually, both in vivo and in vitro studies indicated that nanogels remarkably inhibited in situ tumor growth and hindered metastatic tumor recurrence, offering an alternative possibility for clinical intervention.

Turbulence induced shear controllable synthesis of nano FePO4 irregularly-shaped particles in a counter impinging jet flow T-junction reactor assisted by ultrasound irradiation.

FePO4 (FP) particles with a mesoporous structure amalgamated by nanoscale primary crystals were controllably prepared using an ultrasound-intensified turbulence T-junction microreactor (UTISR). The use of this type of reaction system can effectively enhance the micro-mixing and remarkably improve the mass transfer and chemical reaction rates. Consequently, the synergistic effects of the impinging streams and ultrasonic irradiation on the formation of mesoporous structure of FP nanoparticles have been systematically investigated through experimental validation and CFD simulation. The results revealed that the FP particles with a mesoporous structure can be well synthesised by precisely controlling the operation parameters by applying ultrasound irradiation with the input power in the range of 0-900 W and the impinging stream volumetric flow rate in the range of 17.15-257.22 mL·min-1. The findings obtained from the experimental observation and CFD modelling has clearly indicated that there exists a strong correlation between the particle size, morphology, and the local turbulence shear. The application of ultrasonic irradiation can effectively intensify the local turbulence shear in the reactor even at low Reynolds number based on the impinging stream diameter (Re < 2000), leading to an effective reduction in the particle size (from 273.48 to 56.1 nm) and an increase in the specific surface area (from 21.97 to 114.97 m2·g-1) of FP samples. The FPirregularly-shaped particles prepared by UTISR exhibited a mesoporous structure with a particle size of 56.10 nm, a specific surface area of 114.97 m2·g-1and a total pore adsorption volume of 0.570 cm3·g-1 when the volumetric flow rate and ultrasound power are 85.74 mL·min-1and 600 W, respectively.

Prediction of enhanced drug solubility related to clathrate compositions and operating conditions: Machine learning study.

Although complexation technique has been documented as a promising strategy to enhance the dissolution rate and bioavailability of water-insoluble drugs, prediction of the enhanced drug solubility related to clathrate compositions and operating conditions is still a challenge. Herein, clathrate compositions (drug content (DC), drug molecular weight (M) and molar ratio (Ratio)), operating conditions (drug concentration (C), pH, pressure (P), temperature (T) and dissolution time (t)) under the different excipients (PEG, PVP, HPMC and cyclodextrin) as main solubilizers of the clathrates condition as input parameters were used to predict two indexes (drug dissolved percentage and dissolution efficiency) simultaneously through machine learning methodfor the first time. The results show that PVP as the main solubilizer of clathrates had higher prediction accuracy to the drug dissolved percentage, and HPMC as the main solubilizer of clathrates had higher prediction accuracy to the drug dissolution efficiency. In addition, the influence of various factors and interactions on the target variables were analyzed. This study affords achievable hints to the quantitative prediction of the drug solubility affected by various compositions and different operating conditions.

Research on the risk transmission mechanism of international construction projects based on complex network.

The risk transmission process between international construction projects largely contributes to the dilemma of risk management of international construction projects. Firstly, this paper adopts methods such as literature review and brainstorming to identify the risks in international construction projects from all aspects and all stages. Connections between risks is built by the Delphi method and further construct the international construction project risk network. Combined with "ucinet", a network visualization analysis tool, overall feature parameters and local feature parameters are presented for analysis as the focus. Starting from this, the risk transmission in complex construction projects is analyzed to identify key risks and transmission relationships and reveal inherent laws of risk transmission. Accordingly, when formulating risk prevention strategies for international engineering projects, it is proposed that measures to curb risk transmission should be effectively adopted from both key risks and their transmission relationships.