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Photodynamic therapy (PDT) is an emerging cancer treatment combining light, oxygen, and a photosensitizer (PS) to produce highly cytotoxic reactive oxygen species that cause cancer cell death. However, most PSs are hydrophobic molecules that have poor water solubility and cannot target tumor tissues, causing damage to normal tissues and cells during PDT. Thus, there is a substantial demand for the development of nanocarrier systems to achieve targeted delivery of PSs into tumor tissues and cells. This review summarizes the research progress in PS delivery systems for PDT treatment of tumors and focuses on the recent design and development of multifunctional nanoparticles as PS delivery carriers for enhanced PDT. These multifunctional nanoparticles possess unique properties, including tunable particle size, changeable shape, stimuli-responsive PS activation, controlled PS release, and hierarchical targeting capability. These properties can increase tumor accumulation, penetration, and cellular internalization of nanoparticles to achieve PS activation and/or release in cancer cells for enhanced PDT. Finally, recent developments in multifunctional nanoparticles for tumor-targeted PS delivery and their future prospects in PDT are discussed. [ABSTRACT FROM AUTHOR]

Nanotechnology has demonstrated great promise for the development of more effective and safer cancer therapies. We recently developed a highly selective inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML). However, the poor drug-like properties were hurdles to its further clinical development. Herein, we re-investigate it by conjugating an amphiphilic polymer and self-assembling into a nanoparticle (NP) with a high loading (~10.3%). The formulation greatly improved its solubility and drastically extended its circulation half-life from ~5.3 to ~117 h (>20-fold). In the 150 days long-term engraftment model experiment, long intravenous dosing intervals of the NPs (every 4 or 8 days) exhibited much better survival and negligible toxicities as compared to daily oral administration of the inhibitor. Moreover, the NPs showed excellent inhibition of tumor growth in the subcutaneous xenograft model. All results suggest that the ultra-long circulating pro-drug NP may provide an effective and safe therapeutic strategy for BCR-ABL-positive CML. The poor solubility and pharmacokinetics of potent small molecular inhibitors often represent formidable hurdles for their clinical development. We recently synthesized a highly selective small molecular inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML), which shows much better selectivity than FDA-approved BCR-ABL inhibitors but may not be suitable for further clinical translation due to its water insolubility and short circulation half-life. Herein, we conjugated this new inhibitor to an amphiphilic polymer through a pH-responsive linker, which can self-assemble into pro-drug nanoparticles (NPs). The pro-drug NP formulation drastically improved the inhibitor's solubility and extended its circulation half-life from ~5.3 h to ~117 h (>20-fold increase), leading to superior anti-tumor effects in CML engraftment and xenograft models. Our findings suggest that the ultra-long circulating pro-drug NP strategy may revive the small molecular inhibitors with potent biological activities but unacceptable pharmacological properties for cancer treatment. Unlabelled Image [ABSTRACT FROM AUTHOR]

The diffusion angle of the air jet and the optimal pitch angle (OPA) of the jet fan are studied and compared through turbulent jet theory and FLUENT numerical simulation in this paper. The optimal design pitch angle of jet fans with different outlet diameters and velocities is systematically provided, rather than based on a specific outlet diameter and velocity of the jet fan or only put forward a rough range. The results show that, tilting the fan outlet with a certain angle can reduce the wall shear stress (WSS) and improve the pressure-rise coefficient. The full diffusion angle (FDA) is greatly influenced by the outlet diameter and velocity, while the semi-diffusion angle (SDA) is relatively steady and fluctuates around 6°. Meanwhile, the OPA is hardly affected by the outlet velocity and mainly influenced by the outlet diameter. The OPA is 8° for the jet fan with the diameter less than or equal to 900 mm and 6° for the jet fan diameter more than 900 mm. Moreover, the pressure-rise coefficient will be improved under the OPA and the relative increase rate is between 5.9% and 44.5% compared with that of no pitch angle. This study can provide reference and guidance for the performance research of alternative jet fans in fire case and the optimization design of ventilation systems in road tunnels. • Installation of jet fans should be optimized to realize energy saving. • Semi-diffusion angles of air jets are relatively steady and fluctuate around 6°. • Pressure-rise coefficients of jet fans will be improved when pitch angles exist. • Optimal pitch angles of jet fans are mainly influenced by the outlet diameter. [ABSTRACT FROM AUTHOR]

Abstract\n摘要\nPLAIN LANGUAGE SUMMARYWhile CLIL programmes have been extensively researched for their impact on L2 learning outcomes, the relationship between young learners’ L2 proficiency and subject knowledge has received less attention. This study aimed to address this research gap by examining the science content knowledge of two cohorts of Grade 5 students (n = 100) from two primary schools in China, with one school implementing a CLIL science programme and the other offering a conventional science programme. The study also investigated the correlation between science achievement and L2 proficiency, measured by assessing learners’ English speaking, listening, reading, and writing skills using the Cambridge Young Learners English Tests. Science knowledge was evaluated with a tailored test aligned with the National Science Curriculum. Results indicated no statistically significant differences in science achievement between CLIL and non-CLIL students, with the former achieving higher mean scores. We also found a significant positive correlation between science knowledge and overall L2 proficiency. Notably, receptive language skills significantly correlated with science scores, while productive language skills did not. These findings provide positive evidence for the potential effectiveness of CLIL programmes in the primary education setting in China.目前大量研究关注内容语言融合教学(CLIL)对学习者外语学习的效果, 只有少数研究关注 CLIL 课程中外语学习和学科知识学习之间的关系。因此, 本研究以两所中国小学共100名学生为研究对象, 比较 CLIL 课程和非 CLIL 课程环境下学生的科学知识水平, 并考察学习者外语水平和学科知识的相关性。本研究中的两所学校一所采用中英双语开展科学课教学, 另一所提供中文科学课程。研究者使用剑桥青少年英语测试评估学生的口语、听力、以及阅读写作技能, 采用根据国家课程标准自主开发的科学测试卷评估学生的科学知识。数据分析结果显示接受 CLIL 课程的学生和未接受 CLIL 课程的学生在科学知识上没有显著差异, 但是 CLIL 课程中学生的科学知识均分更高。同时, 学生的科学知识和外语能力之间呈显著正相关。在细分的语言技能上, 学生的接受性二语技能与科学知识呈显著正相关, 而表达性二语技能与科学知识之间无显著相关。本研究结果为在中国的青少年外语课堂中实施 CLIL 教学提供了积极的实证依据。Content and Language Integrated Learning (CLIL) is an educational approach that combines language learning with subject content, such as math, science, history, etc. One of the “selling points” of CLIL is that students can learn both language and subject knowledge at the same time. There has been a large amount of research into the language learning outcomes of CLIL students, but far less research has been conducted to determine if CLIL students can acquire subject content knowledge as effectively as those who learn it in their native language. This study, therefore, compared CLIL and non-CLIL students’ science learning outcomes and investigated if students’ science achievement was related to their English proficiency. The results showed no statistically significant difference in science scores between students learning in English and Chinese, with the former achieving better average scores than the latter. We found a positive relationship between students’ science and English scores, indicating that those with better English proficiency tended to perform well in science, and vice versa. The findings indicate that CLIL has potential in primary schools in China. [ABSTRACT FROM AUTHOR]

Lignin dissolution and the fluid behaviour of reaction systems play important roles in the conversion rate of lignin. This study investigated the solubility of enzymatic hydrolysis lignin (EHL) in 1-butyl-3-methylimidazole bisulphate ethanol solutions ([BMIM]HSO4/ethanol) and the dynamic shear rheological characterisation of EHL-[BMIM]HSO4/ethanol. Different with [BMIM]HSO4/water, [BMIM]HSO4/ethanol exhibited excellent abilities to dissolve EHL at [BMIM]HSO4% 20%–90%, with the maximum EHL solubility obtained at 40%–70%. The dynamic shear rheological characterisation strongly depended on temperatures, [BMIM]HSO4% and EHL%, exhibited as pseudoplastic fluid at higher [BMIM]HSO4% and EHL%, and Dilatant fluid at lower [BMIM]HSO4% and EHL%. Adjusting an appropriate [BMIM]HSO4% and EHL%, EHL-[BMIM]HSO4/ethanol was Newtonian fluid with the viscosity stable. EHL was regenerated from EHL-[BMIM]HSO4/ethanol without obvious changes in the chemical structure and thermal behaviour. This study provided ideas for the design of the [BMIM]HSO4/ethanol system and the optimisation of conversion processes for the economic utilisation of lignin. [ABSTRACT FROM AUTHOR]

Background: Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. Methods: We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood–brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. Results: The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. Conclusion: The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders. [ABSTRACT FROM AUTHOR]

Colony stimulating factor 1 receptor kinase (CSF1R) plays an integral role in tumor-associated macrophage repolarization and has emerged as a novel therapeutic target for cancer immunotherapy. Most of the current CSF1R kinase inhibitors lack selectivity between CSF1R kinase and other type III growth factor receptor members. Herein, we report a potent and selective CSF1R inhibitor 18h , which displays an IC 50 value of 5.14 nM against CSF1R and achieves selectivity over other type III receptor tyrosine kinases (>38-fold). 18h inhibits the phosphorylation of CSF1R and its downstream signaling pathway in RAW264.7, THP-1, and M–NFS–60 cells. Treatment with this compound leads to alteration of the macrophage polarization in RAW264.7 macrophages in a dose-dependent manner. In vivo, 18h demonstrates acceptable pharmacokinetic profiles and suppresses the tumor growth in a mouse xenograft model inoculated with M–NFS–60 cells. [Display omitted] • Medicinal chemistry optimization leads to a novel CSF1R kinase inhibitor 18h • 18h increases the M1 macrophage phenotype dose-dependently in RAW264.7 macrophages • 18h inhibits the tumor growth in a M–NFS–60 tumor xenograft model [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor (PDGF) is one of the most important cytokines associated with pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). PDGF receptor (PDGFR) inhibition exerted therapeutic effects on PAH in clinical trials, but serious side effects warrant the withdrawal of existing drugs. In this study, a novel highly selective PDGFR inhibitor WQ-C-401 was developed, and its effects on PDGFR signaling pathway and pulmonary vascular remodeling in PAH were investigated. Cell proliferation assays and Western blot analysis of PDGFRα/β phosphorylation showed that WQ-C-401 inhibited PDGFR-mediated cell proliferation assay and suppressed PDGFR phosphorylation in a concentration-dependent manner. DiscoverX's KinomeScanTM technology confirmed the good kinome selectivity of WQ-C-401 (S score (1) of PDGFR = (0.01)). In monocrotaline (MCT)-induced PAH rats, intragastric administration of WQ-C-401 (25, 50, 100 mg/kg/d) or imatinib (50 mg/kg/d, positive control) significantly decreased right ventricular systolic pressure (RVSP). Histological analysis demonstrated that WQ-C-401 inhibited pulmonary vascular remodeling by reducing muscularization and fibrosis, as well as alleviated right ventricular hypertrophy in MCT-treated rats. In addition, WQ-C-401 suppressed MCT-induced cell hyperproliferation and CD68+ macrophage infiltration around the pulmonary artery. In vitro , WQ-C-401 inhibited PDGF-BB-induced proliferation and migration of human pulmonary arterial smooth muscle cells (PASMCs). Moreover, Western blot analysis showed that WQ-C-401 concertration-dependently inhibited PDGF-BB-induced phosphorylation of ERK1/2 and PDGFRβ Y751, decreased collagen Ⅰ synthesis and increased alpha smooth muscle actin (α-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C-401 is a selective and potent PDGFR inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling. [ABSTRACT FROM AUTHOR]

Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene–co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053. [ABSTRACT FROM AUTHOR]

Vibrio vulnificus (V. vulnificus) infection-associated multiple antibiotic resistance has raised serious public health concerns. Recently, nanosponges (NSs) have been expected to provide innovative platforms for addressing antibacterial and drug-resistant challenges by targeting various pore-forming toxins (PFTs). In the present study, we constructed NSs to explore the effects and possible mechanism of recombinant V. vulnificus hemolysin (rVvhA)-induced injuries. In vitro, NSs significantly reversed rVvhA-induced apoptosis and necrosis, and improved toxin-induced intracellular reactive oxygen species (ROS) production, adenosine triphosphate (ATP) depletion, and apoptosis signaling pathway disruption. To explore the clinical translation potential of NSs, we established VvhA-induced septicemia and wound infection mouse models, respectively, and further found NSs could notably attenuate rVvhA-induced acute toxicity and septicemia-associated inflammation, as well as local tissue damage. In a conclusion, NSs showed excellent protective effects against rVvhA-induced toxicity, thus providing useful insights into addressing the rising threats of severe V. vulnificus infections. [ABSTRACT FROM AUTHOR]

In vivo imaging of tumor-related mRNA has prosperous prospects for tumor diagnosis. Given the low expression levels of tumor-related mRNA at early stages of cancer, its in vivo amplified imaging still requires more efforts. Herein, we report a novel cofactor self-supplying and self-feedback DNAzyme (Dz) nanodevice (SFDND) for imaging of tumor-related mRNA in vitro and in vivo with cascade signal amplification ability. The SFDND is built by assembling a hairpin DNA recognition probe with locked Dz and a DNA trigger-incorporated fluorogenic hairpin substrate probe on ZnO@polydopamine nanoparticles (ZnO@PDA NPs). After entering cells, ZnO@PDA NPs are decomposed in acidic lysosomes to release nucleic acids and DNAzyme cofactor Zn2+. Intracellular hybridization of target mRNA with the released hairpin DNA recognition probe activates Dz, which can cyclically cleave hairpin substrate probes to liberate many fluorophores and substrate segments containing DNA triggers, thereby generating amplified fluorescence signal. Moreover, each DNA trigger within the released substrate segments can also bind with the hairpin DNA recognition probe to activate Dz, which induces further signal amplification via a feedback mechanism. This SFDND achieves ∼103-fold improvement in detection sensitivity over conventional non-feedback Dz nanodevice. It could accurately discriminate tumor cells from normal cells and selectively diagnose tumors in vivo during different stages of tumor growth by means of mRNA imaging. The proposed SFDND may be extended for amplified sensing and imaging of other low-abundance targets (e.g., microRNAs and aptamer substrates) by simply switching corresponding nucleic acid sequences, thus possesses promising application in basic biomedical research and disease diagnosis. [Display omitted] • A novel cofactor self-supplying and self-feedback DNAzyme nanodevice is developed. • It achieves ∼103-fold improvement in assay sensitivity over conventional DNAzyme nanodevices. • It has been successfully applied to diagnose tumors in vitro and in vivo based on mRNA imaging. • This work promises an attractive strategy for sensing and imaging of biomarkers in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Schematic illustration of the preparation, pH-sensitive release, cellular uptake and concentration–time profile of GNA@Zein-PDA NPs. As one of the active pharmaceutical ingredients in Gamboge, Gambogenic acid (GNA) has shown diverse anti-tumor activities. To reduce the vascular irritation of GNA and improve its water solubility, tumor targeting, and bioavailability, GNA loaded Zein nanoparticles (GNA@Zein NPs) was further coated by polydopamine (PDA) to develop GNA@Zein-PDA NPs by anti-solvent precipitation and surface modification. The results showed that particle size and Zeta potential of GNA@Zein-PDA NPs were about 310 nm and −40.8 mV with core–shell morphology confirmed by TEM. GNA@Zein-PDA NPs increased the water solubility of GNA by more than 700 times and showed pH-sensitive release behavior in PBS with pH 6.86. In vitro cytotoxicity tests showed that GNA@Zein-PDA NPs had higher inhibitory activity on HepG2 cells than free GNA, and their IC 50 were 1.59 μg/mL and 9.89 μg/mL, respectively. Additionally, the hemolysis and vascular irritation assay showed that GNA@Zein-PDA NPs had good cytocompatibility and reduced the irritation of GNA to blood vessels. Moreover, the in vivo pharmacokinetic experiments exhibited that the C max and AUC 0-t of GNA@Zein-PDA NPs were significantly improved approximately by 2.09-fold and 3.48-fold over that of GNA, respectively. In conclusion, GNA@Zein-PDA NPs solve many defects of GNA and provide a tumor-targeting drug delivery for GNA. [ABSTRACT FROM AUTHOR]

Phosphoinositol 3-kinases (PI3Ks) γ and δ are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3Kγ/δ has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3Kγ/δ dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model. [Display omitted] • Medicinal chemistry optimization led to a novel potent PI3Kγ/δ dual inhibitor 15u. • 15u exhibited strong potencies against PI3Kγ/δ in biochemical and cellular assays. • 15u repolarized M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. • 15u inhibited the tumor growth in a MC38 xenograft mouse model. [ABSTRACT FROM AUTHOR]

PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC 50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10–1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory. [ABSTRACT FROM AUTHOR]

Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong potency against purified PDGFRα (IC 50 : 132 nM) but not structurally similar PDGFRβ, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFRα revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFRα driving Chronic Eosinophilic Leukemia (CEL) cell line EOL-1 through strong blockage of PDGFRα mediated signaling pathways, arresting cell cycle progression, and induction of apoptosis. Furthermore, compound 15i effectively suppressed the EOL-1 tumor progression in the xenograft model and increased the survival rate in the engraftment tumor model. [ABSTRACT FROM AUTHOR]

Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC. [ABSTRACT FROM AUTHOR]

• The graph-guided-sparsity-inducing penalty can strengthen the bioluminescent energy spatial aggregation and relation, since it reflects not only the non-linear inverse relationship between bioluminescent energy deviation and their distance for any two nodes, but also the connection between the local bioluminescent energy clusters consisting of multiple the nearest adjacent nodes. • The GGHR method based on three constraints (sparsity, smoothness, graph-guided penalty) can better balance the sparsity, smoothness and morphological characteristics of the bioluminescence targets. • Dual decomposition and Nesterov's smoothing technique are used to provide an efficient optimization approach for solving the non-separable and non-smooth constrain problem. • The GGHR method can effectively alleviate the ill-posed inverse problem. • The GGHR method performs well in spatial location, morphology and bioluminescent energy recovery and preclinical practicality. Background and objective: Bioluminescence tomography (BLT) is a powerful and sensitive imaging technique having great potential in preclinical application, such as tumor imaging, monitoring and therapy, etc. Regularization plays an important role in BLT reconstruction for considering the priori information to overcome the inherent ill-posedness of the inverse problem. Therefore, well-designed regularization term and sophisticated algorithm for solving the consequent optimization problem are key to improve the BLT quality. Methods: To balance the sparsity, smoothness and morphological characteristics of the bioluminescence targets, we constructed a novel Graph-Guided Hybrid Regularization (GGHR) method by combining graph-guided penalty term with L 1 and L 2 norm regularizer. To solve the corresponding minimization problem with hybrid penalties, the dual decomposition and Nesterov's smoothing technique were adopted to decouple and transform the non-separable and non-smooth graph-guided penalty term into a differential smooth approximation form, which was solved by the fast iterative shrinkage thresholding algorithm. Results: The performance of the proposed GGHR method was verified and evaluated through a series of simulation, phantom and in vivo experiments. The comparison results demonstrated that the GGHR method outperformed current mainstream reconstruction algorithms in spatial localization, morphology recovery and in vivo practicality. Conclusions: The proposed GGHR method is a robust and practicality reconstruction algorithm for further highlighting the positive effect of hybrid regularization on BLT applications. [ABSTRACT FROM AUTHOR]

Pollution of trace metals was evaluated in the soil and plant samples collected from lead–zinc smelting areas in Huixian of Northwest China. The soil samples from the arable lands surrounding the smelting sites contained high levels of Cd, Pb, and Zn, which were 6.59–237, 3.27–218 and 0.375–2.38 times respectively above the background values in the study areas, indicating a certain extent of spreading of trace metal pollution. The main causes to the dispersion of pollution were proposed to be the continuous wastewater irrigation and wind transport of dust. The geo-accumulation index ( Igeo ) revealed that Cd and Pb were heavy pollutants. The correlation analysis proved a correlation between soil properties and individual metal, suggesting the significant effect of soil properties on trace metal pollution. A two step sequential extraction showed that heavy metals were poorly labile under natural conditions. However, extraction with complexing agent generated significant amounts of metals, suggesting they were potentially mobilizable. The levels of Cu, Cd, Pb, and Zn in aerial parts of typical plants ranged from 0.048 to 19.9, 0.122 to 8.17, 11.1 to 48.6, and 0.646 to 85.8 mg kg − 1 , respectively. The accumulation ability changed in an order as: Cd > Zn > Cu > Pb and a high level was detected in maize (Cd), ainsliaea (Cd), goosegrass herb (Zn), and poplar (Zn). Pb and Cd were potentially risky to local inhabitants. Apparently, some effective measures may be necessary to treat trace metal pollution in soil and to reduce metal translocation from soil to edible crops. [ABSTRACT FROM AUTHOR]

Cyanobacteria-derived toxin microcystin-LR (MCLR) has been widely investigated in its effects on normal cells, there is little information concerning its effects on cancer cells. In the present study, the SMMC-7721 human liver cancer cell line treated with MCLR was used to investigate the change of PP2A, cytoskeleton rearrangement, phosphorylation levels of PP2A substrates that related with cytoskeleton stability and explored underlying mechanisms. Here, we confirmed that MCLR entered into SMMC-7721 cells, bound to PP2A/C subunit and inhibited the activity of PP2A. The upregulation of phosphorylation of the PP2A/C subunit and PP2A regulation protein α4, as well as the change in the association of PP2A/C with α4, were responsible for the decrease in PP2A activity. Another novel finding is that the rearrangement of filamentous actin and microtubules led by MCLR may attribute to the increased phosphorylation of HSP27, VASP and cofilin due to PP2A inhibition. As a result of weakened interactions with PP2A and alterations in its subcellular localization, Rac1 may contribute to the cytoskeletal rearrangement induced by MCLR in SMMC-7721 cells. The current paper presents the first report demonstrating the characteristic of PP2A in MCLR exposed cancer cells, which were more susceptible to MCLR compared with the normal cell lines we previously found, which may be owing to the absence of some type of compensatory mechanisms. The hyperphosphorylation of cytoskeleton-associated proteins and Rac1 inactivation which were induced by inhibition of PP2A are shown to be involved in cytoskeleton rearrangement. [ABSTRACT FROM AUTHOR]

Thioredoxins (Trx proteins) are a family of small, highly-conserved and ubiquitous proteins that play significant roles in the resistance of oxidative damage. In this study, a homologue of Trx was identified from the cDNA library of tentacle of the jellyfish Cyanea capillata and named CcTrx1. The full-length cDNA of CcTrx1 was 479 bp with a 312 bp open reading frame encoding 104 amino acids. Bioinformatics analysis revealed that the putative CcTrx1 protein harbored the evolutionarily-conserved Trx active site 31CGPC34 and shared a high similarity with Trx1 proteins from other organisms analyzed, indicating that CcTrx1 is a new member of Trx1 sub-family. CcTrx1 mRNA was found to be constitutively expressed in tentacle, umbrella, oral arm and gonad, indicating a general role of CcTrx1 protein in various physiological processes. The recombinant CcTrx1 (rCcTrx1) protein was expressed in Escherichia coli BL21 (DE3), and then purified by affinity chromatography. The rCcTrx1 protein was demonstrated to possess the expected redox activity in enzymatic analysis and protection against oxidative damage of supercoiled DNA. These results indicate that CcTrx1 may function as an important antioxidant in C. capillata. To our knowledge, this is the first Trx protein characterized from jellyfish species. [ABSTRACT FROM AUTHOR]

• Constructions of tunnel complexes are in the ascendant. • Desirable performance of alternative jet fans in curved tunnels discovered. • Optimal installation method of jet fans in curved tunnels developed. • Relationship between wall shear stress and tunnel radius revealed. Constructions of underground complex road networks or tunnel complexes all over the world are in the ascendant. However, very few countries have developed specific recommendations or standards for the ventilation design of these special underground traffic facilities. Therefore, ventilation strategies in curved road tunnels, which is the typical characteristic of tunnel complexes, were mainly concerned and investigated by ANSYS Fluent in this paper. Flow field, pressure-rise coefficient (PC) and wall shear stress (WSS) were mainly compared and analyzed. The results show that the PC of alternative jet fans present a desirable performance than traditional jet fans, either for improving flow field and PC or decreasing WSS. In addition, the wall shear stress in curved road tunnels was especially analyzed, and both the confined WSS and the impactive WSS were defined. Besides, the confined WSS dominates in tunnels with large radius and the impactive WSS dominates in tunnels with small radius. Tilting the outlet of jet fans toward the tunnel floor and the convex side of tunnels with an optimal angle can reduce the confined and impactive WSSes, respectively. Moreover, the highest PC will be obtained by reducing the two types of WSS simultaneously. Findings of this study can provide significant reference for the design of longitudinal ventilation systems in curved road tunnel complexes. [ABSTRACT FROM AUTHOR]

• The fire smoke backflow in inclined tunnel is mainly driven by downstream length. • A non-dimensional empirical correlation of back-layering length and downstream length is established. • A new prediction formula of back-layering length account for tunnel slopes and downstream length is developed. To investigate the vehicle fire hazard at different locations in inclined tunnels, the effect of longitudinal fire locations on smoke behavior characteristics induced by inclined tunnel fires was proposed by simulation and theoretical analysis. A series of tunnel models with slope of 4% was conducted by Fire Dynamics Simulator (FDS) software for fire simulation, in which three fire scenarios were considered corresponding to the variation of fire location, upstream length and downstream length respectively. The results show that smoke back-layering length drops progressively with increasing of downstream length, and upstream inlet airflow velocity is linearly positively correlated with downstream length, while the upstream length has a limited impact on smoke movement. A new prediction equation of the dimensionless smoke back-layering length account for downstream length and tunnel slope was established, through the addition of height difference between fire source and downstream exit. The established correlation shows that the dimensionless smoke back-layering length is logarithmically related to cubic power of downstream length, and the predicted results agreed well with simulated data as tunnel slope from 3.5% to 7.5%. The results can provide beneficial suggestion in ventilation system design and emergency evacuation for inclined tunnels. [ABSTRACT FROM AUTHOR]

In order to analyze the feasibility of setting bypass tunnel in urban highway tunnel for pollutant purification and dust removal, a physical model including main tunnel and bypass tunnel is established based on ICEM and Fluent numerical simulation software. The purpose of this paper is to analyze the influence of the angle between the bypass tunnel and the main tunnel on the velocity field, pressure distribution and the efficiency of air flow from main tunnel to bypass tunnel. The results show that low-speed and low-pressure areas are generated in the main tunnel which is corresponding to the bypass tunnel entrance (short passageway), and vortices are formed. After the tunnel is opened to traffic, this area will become a pollutant accumulation zone. The bypass tunnel shunting efficiency will increase as the angle decreases. In engineering design, under conditions that meet the safety and economics of the project construction, the included angle can be set to the minimum but not less than 30° to achieve the maximum efficiency. • Purification of exhaust gas in road tunnels by bypass tunnel. • The main tunnel section corresponding to the bypass tunnel will become the accumulation area of pollutants. • Decreasing the angle of the bypass tunnel can promote the gas to enter the bypass tunnel. • The efficiency increases and then trends to be stable as the bypass tunnel angle decreases. [ABSTRACT FROM AUTHOR]

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (Pf PI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC 50 : 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC 50 : 25.1 nM). CHMFL-PI4K-127 displays high selectivity against Pf PI4K over human lipid and protein kinase. In addition, it exhibits EC 50 values of 23–47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria. Image 1 • A novel pharmacophore based Pf PI4K inhibitor CHMFL-PI4K-127 was discovered. • The inhibitor exhibited high selectivity against Pf PI4K over human kinase. • The inhibitor potently inhibited a panel of drug-resistant strains of P. falciparum. • The inhibitor exhibited antimalarial efficacy in both blood stage and liver stage. [ABSTRACT FROM AUTHOR]