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Fusarium graminearum is a causal agent of wheat scab disease and a producer of deoxynivalenol (DON) mycotoxins. Treatment with exogenous cyclic adenosine monophosphate (cAMP) increases its DON production. In this study, to better understand the role of the cAMP-protein kinase A (PKA) pathway in F. graminearum, we functionally characterized the PKR gene encoding the regulatory subunit of PKA. Mutants deleted of PKR were viable, but showed severe defects in growth, conidiation and plant infection. The pkr mutant produced compact colonies with shorter aerial hyphae with an increased number of nuclei in hyphal compartments. Mutant conidia were morphologically abnormal and appeared to undergo rapid autophagy-related cell death. The pkr mutant showed blocked perithecium development, but increased DON production. It had a disease index of less than unity and failed to spread to neighbouring spikelets. The mutant was unstable and spontaneous suppressors with a faster growth rate were often produced on older cultures. A total of 67 suppressor strains that grew faster than the original mutant were isolated. Three showed a similar growth rate and colony morphology to the wild-type, but were still defective in conidiation. Sequencing analysis with 18 candidate PKA-related genes in three representative suppressor strains identified mutations only in the CPK1 catalytic subunit gene. Further characterization showed that 10 of the other 64 suppressor strains also had mutations in CPK1. Overall, these results showed that PKR is important for the regulation of hyphal growth, reproduction, pathogenesis and DON production, and mutations in CPK1 are partially suppressive to the deletion of PKR in F. graminearum.

The cathode interfacial layer (CIL) plays a vital role in enhancing the efficiency and lifetime performance of bulk heterojunction (BHJ) polymer solar cells (PSCs). Here, we compared the use of various organic semiconducting molecules, tris(8-hydroxyquinolinato) aluminum (Alq3), bathocuproine (BCP) and 1,3,5-tri(m-pyrid-3-yl-phenyl)benzene (TmPyPB), as CILs in PSCs and analyzed their influence on device performance. Compared to the inorganic LiF CIL-based PSCs, significantly higher photovoltaic performance was observed by using these organic CILs in both PTB7:PC71BM and P3HT:PC61BM PSCs. Specifically, TmPyPB CIL-based devices exhibit superior device stability and high power conversion efficiency (PCE) up to 7.96%. A systematic study on the effects of Frontier orbital energy levels, surface morphology, and electron mobility of CILs suggests that a relatively coarse interface morphology would be helpful in the formation of high-density interfacial defect states for efficient electron extraction and a high mobility is of central importance in facilitating electron collection for high PCEs. Moreover, a synergistic effect between the inorganic LiF and organic molecules in the dual-CIL could contribute to the further enhancement of PSC efficiency (8.01%) and ambient stability. This work reveals fundamental principles in regulating the functions of CILs and would hopefully promote the investigation and development of ideal organic CILs for high-performance PSCs.

In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFRL858R/T790M and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance via its simultaneous inhibition of their kinase activities. Comparison with EGFRL858R/T790M and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFRL858R/T790M and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFRL858R/T790M-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.

The mechanical properties of the aorta tissue is not only important for maintaining the cardiovascular health, but also is closely related to the development of cardiovascular diseases. There are obvious differences between the ventral and dorsal tissues of the descending aorta. However, the cause of the difference is still unclear. In this study, a biaxial tensile approach was used to determine the parameters of porcine descending aorta by analyzing the stress-strain curves. The strain energy functions Gasser-Ogden-Holzapfel was adopted to characterize the orthotropic parameters of mechanical properties. Elastic Van Gieson (EVG) and Sirius red stain were used to observe the microarchitecture of elastic and collagen fibers, respectively. Our results showed that the tissue of descending aorta had more orthotropic and higher elastic modulus in the dorsal region compared to the ventral region in the circumferential direction. No significant difference was found in hyperelastic constitutive parameters between the dorsal and ventral regions, but the angle of collagen fiber was smaller than 0.785 rad (45°) in both dorsal and ventral regions. The arrangement of fiber was inclined to be circumferential. EVG and Sirius red stain showed that in outer-middle membrane of the descending aorta, the density of elastic fibrous layer of the ventral region was higher than that of the dorsal region; the amount of collagen fibers in dorsal region was more than that of the ventral region. The results suggested that the difference of mechanical properties between the dorsal and ventral tissues in the descending aorta was related to the microstructure of the outer membrane of the aorta. In the relatively small strain range, the difference in mechanical properties between the ventral and dorsal tissues of the descending aorta can be ignored; when the strain is higher, it needs to be treated differently. The results of this study provide data for the etiology of arterial disease (such as arterial dissection) and the design of artificial blood vessel.动脉组织的力学性能对于维持心血管健康具有重要意义，并与心血管相关疾病的发生发展密切相关。主动脉腹侧和背侧组织力学性能之间存在显著差异，但缺乏量化的力学性能参数，且其成因尚不清楚。本文以猪降主动脉腹侧与背侧组织为研究对象，通过双轴拉伸方法获取应力-应变曲线，分析组织正交各向异性，采用 Gasser-Ogden-Holzapfel 型应变能函数描述动脉组织力学性能参数，采用 Elastic Van Gieson（EVG）法和天狼星红染色法观测动脉组织弹性纤维和胶原纤维显微结构。结果表明，与降主动脉腹侧组织相比，降主动脉背侧组织表现出更明显的正交各向异性，且在周向上的弹性模量明显大于降主动脉腹侧组织。降主动脉腹侧和背侧组织的超弹本构参数之间差异均无统计学意义，但几乎所有降主动脉组织的纤维角度都小于 0.785 rad（45°），胶原纤维的排列更趋于周向。EVG 和天狼星红染色显示降主动脉腹侧外-中膜弹性纤维层密度明显高于背侧组织，外-中膜胶原纤维背侧多于腹侧。结果提示，猪降主动脉背侧组织与腹侧组织之间的力学性能差异与外-中膜组织中的微观结构有关。在相对较小的应变范围内，可忽略降主动脉腹侧与背侧组织力学性能的差异；当应变较高时，则需区别对待。本研究结果可为动脉疾病（如动脉夹层）的成因以及人工血管设计等提供数据参考。.

Acute lung injury (ALI) is often caused by systemic inflammatory responses. Targeting the myeloid differentiation protein 2/toll-like receptor 4 (MD2-TLR4) complex may be a promising way to treat Gram-negative bacterial-induced inflammatory disorders. In this study, we report the design and synthesis of a new series of 3-(indol-5-yl)-indazoles, which were evaluated for their anti-inflammatory activities in macrophages. Among the analogues generated, the promising 3-(indol-5-yl)-indazole analogue 22m inhibited lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in macrophages with IC

A series of novel symmetric and asymmetric allylated mono-carbonyl analogs of curcumin (MACs) were synthesized using an appropriate synthetic route and evaluated experimentally thru the LPS-induced expression of TNF-α and IL-6. Most of the obtained compounds exhibited improved water solubility as a hydrochloride salt compared to lead molecule 8f. The most active compound 7a was effective in reducing the Wet/Dry ratio in the lungs and protein concentration in bronchoalveolar lavage fluid. Meanwhile, 7a also inhibited mRNA expression of several inflammatory cytokines, including TNF-α, IL-6, IL-1β, and VCAM-1, in Beas-2B cells after Lipopolysaccharide (LPS) challenge. These results suggest that 7a could be therapeutically beneficial for use as an anti-inflammatory agent in the clinical treatment of acute lung injury (ALI).

Piperlongumine (PL), a natural alkaloid isolated from the fruit of long pepper, is known to selectively kill tumor cells while sparing their normal counterparts. However, the cellular target and potent anticancer efficacy of PL in numerous types of human cancer cells have not been fully defined. We report here that PL may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells. By inhibiting TrxR1 activity and increasing intracellular ROS levels, PL induces a lethal endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells. Importantly, knockdown of TrxR1 sensitizes cells to PL treatment, and PL displays synergistic lethality with GSH inhibitors (BSO and Erastin) against gastric cancer cells. In vivo, PL treatment markedly reduces the TrxR1 activity and tumor cell burden. Remarkably, TrxR1 was significantly overexpressed in gastric cancer cell lines and human gastric cancer tissues. Targeting TrxR1 with PL thus discloses a previously unrecognized mechanism underlying the biological activity of PL and provides an in-depth insight into the action of PL in the treatment of gastric cancer.

Traditional GPS receivers usually take a long time to obtain their first position solution in the cold start mode. This paper presents a method for assisting the cold start of GPS receivers by autonomous satellite orbit prediction. In this method, the time-consuming broadcast ephemeris collection process in a traditional cold start is replaced by orbit prediction to obtain the satellite position information required for positioning. Thus, the time to first fix of the receiver can be reduced significantly. In addition, since the traditional orbit prediction algorithms based solely on physics-based models have limited accuracy, a hybrid model composed of dynamic models and artificial neural network models for orbit prediction is proposed to improve the accuracy of the orbit prediction. Taking GPS PRN1 as an example, the simulation results show that, in 75% of cases, the satellite position error after 7 days’ prediction with the dynamic models is less than 162.84 m, but this value can be reduced to 46.06 m with the proposed hybrid model; the improvement rate achieved is approximately 71.71%. Some positioning experiments with simulated satellite signals were conducted to assess the first-fix accuracy of a GPS receiver with the proposed satellite orbit prediction function. The results of this study offer insights for the design of advanced assisted GPS receivers.

Two new building blocks of perylene-embedded benzoazoles containing both rigid 2D-conjugated aromatic rings and flexible branched alkyl chains were designed and facilely synthesized in high yields for organic solar cells (OSCs). With a typical acceptor of diketopyrrolopyrrole, small molecular OSC donors constructed in an acceptor-fused donor–acceptor motif exhibit excellent solubility, stability, and light absorption with tunable frontier orbitals, leading to a power conversion efficiency of up to 2.88% in preliminary OSCs.

Siyang Xiao,1,* Wenxin Zhang,1,* Hongjin Chen,1 Bo Fang,1 Yinda Qiu,2 Xianxin Chen,1 Lingfeng Chen,1 Sheng Shu,1 Yunjie Zhao,1 Zhiguo Liu,1 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; 2College of Life and Environmental Science, Wenzhou University, Wenzhou, Zhejiang, China *These authors contributed equally to this work Purpose: The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. Methods: A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. Results: Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. Conclusion: The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury. Keywords: indanone, acute lung injury, drug design, anti-inflammation, synthesis

The magnetic properties of electrical steels are improved with additions of silicon and aluminum; however, these elements also promote the formation of non-metallic inclusions. The presence of non-metallic inclusions in electrical steels severely affects its magnetic properties. In this work, the effect of cooling rate, superheat, and refractory composition on the formation of non-metallic inclusions has been investigated. The evolution in chemical composition has been reported using a new representation employing pseudo-quinary phase diagrams. It has been found that the concentration of MnO in the non-metallic inclusions plays a big role to control its population density. A critical value has been identified above which it is possible to achieve a large decrease in the total number of non-metallic inclusions in electrical steels, in addition to this, it was also possible to define the influence of cooling rate, superheat, and refractory chemical composition on the composition and population density of non-metallic inclusions. It was found that increasing cooling rate and a change of crucible from alumina-based to MgO-based, both increase the population density of NMI, on the contrary, superheat decreases the population density, depending on the concentration of MnO in the inclusions.

We previously reported a symmetric monocarbonyl analog of curcumin (MACs), C66, which demonstrated potential anti-inflammatory activity and low toxicity. In continuation of our ongoing research, we designed and synthesized 34 asymmetric MACs based on C66 as a lead molecule. A majority of the C66 analogs effectively inhibited LPS induction of TNF-α and IL-6 expression. Additionally, a preliminary SAR was conducted. Furthermore, active compounds 4a11 and 4a16 were found to effectively reduce the W/D ratio in the lungs and the protein concentration in the bronchoalveolar lavage fluid (BALF). Meanwhile, a histopathological examination indicated that these two analogs significantly attenuate tissue injury in the lungs with LPS-induced ALI rats. 4a11 and 4a16 also inhibited mRNA expression of several inflammatory cytokines, including TNF-α, IL-6, IL-1β, COX-2, ICAM-1 and VCAM-1, in the Beas-2B cells after LPS challenge. Altogether, the data exhibit a series of new C66 analogs as promising anti-inflammatory agents for the treatment of LPS-induced ALI.

The cleft nasal deformity is a prevailing problem of complex challenge for plastic surgery, especially in the secondary correction. We mainly chose 40 patients with unilateral secondary cleft lip nasal deformity with alar collapse. Based on biomechanics and anatomy of nasal cartilage, we adapt a Z-plasty with cartilage mucosa using the deformed lateral crus of the upper lateral cartilage to support the collapse of lower lateral cartilage. All of our patients were satisfied with the aesthetic morphology after surgery, so we are confident that this method should be considered as an auxiliary treatment to rhinoplasty.

Myosin light chain kinase (MYLK) is found to catalyze the phosphorylation of myosin light chains (MLC) and regulate invasion and metastasis in some malignancies. However, there is little knowledge on the role of MYLK in hepatocellular carcinoma (HCC), and no studies have been conducted to investigate the mechanisms underlying MYLK-mediated promotion of HCC invasion and metastasis until now. In this study, we investigated the expression of MYLK in 50 pairs of human HCC and adjacent liver specimens. High MYLK expression was significantly correlated with aggressive clinicopathological features including tumor encapsulation, microvascular invasion and metastasis. In vitro assays showed that shRNA-induced MYLK knockdown significantly inhibited the wound-healing ability of HCC cells and the ability to migrate and invade through Matrigel. We next uncovered that MYLK knockdown resulted in a reduction in the number of F-actin stress fibers, disorganization of F-actin architectures and morphological alterations of HCC cells. Phosphorylated MLC, rather than total MLC, was found to be markedly reduced in response to downregulation of MYLK expression, and MYLK-regulated actin cytoskeleton through phosphorylating MLC in HCC cells. In addition, Western blotting assay revealed downregulation of the epithelial marker E-cadherin and upregulation of mesenchymal markers Vimentin, N-cadherin and Snail. Taken together, our findings indicate that MYLK promotes HCC progression by altering cytoskeleton to enhance epithelial-mesenchymal transition (EMT).

Myeloid differentiation protein 2 (MD2), together with Toll-like receptor 4 (TLR4), binds lipopolysaccharide (LPS) with high affinity, inducing the formation of the activated homodimer LPS-MD2-TLR4. MD2 directly recognizes the Lipid A domain of LPS, leading to the activation of downstream signaling of cytokine and chemokine production, and initiation of inflammatory and immune responses. However, excessive activation and potent host responses generate severe inflammatory syndromes such as acute sepsis and septic shock. MD2 is increasingly being considered as an attractive pharmacological target for the development of potent anti-inflammatory agents. In this Keynote review, we provide a comprehensive overview of the recent advances in the structure and biology of MD2, and present MD2 modulators as promising agents for anti-inflammatory intervention.

Fusarium graminearum is a causal agent of wheat scab disease and a producer of deoxynivalenol (DON) mycotoxins. Treatment with exogenous cyclic adenosine monophosphate (cAMP) increases its DON production. In this study, to better understand the role of the cAMP–protein kinase A (PKA) pathway in F. graminearum, we functionally characterized the PKR gene encoding the regulatory subunit of PKA. Mutants deleted of PKR were viable, but showed severe defects in growth, conidiation and plant infection. The pkr mutant produced compact colonies with shorter aerial hyphae with an increased number of nuclei in hyphal compartments. Mutant conidia were morphologically abnormal and appeared to undergo rapid autophagy‐related cell death. The pkr mutant showed blocked perithecium development, but increased DON production. It had a disease index of less than unity and failed to spread to neighbouring spikelets. The mutant was unstable and spontaneous suppressors with a faster growth rate were often produced on older cultures. A total of 67 suppressor strains that grew faster than the original mutant were isolated. Three showed a similar growth rate and colony morphology to the wild‐type, but were still defective in conidiation. Sequencing analysis with 18 candidate PKA‐related genes in three representative suppressor strains identified mutations only in the CPK1 catalytic subunit gene. Further characterization showed that 10 of the other 64 suppressor strains also had mutations in CPK1. Overall, these results showed that PKR is important for the regulation of hyphal growth, reproduction, pathogenesis and DON production, and mutations in CPK1 are partially suppressive to the deletion of PKR in F. graminearum.

Acute lung injury (ALI) has a high lethality rate, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute most to tissue deterioration in cases of ALI. In this study, we designed and synthesized a new series of thiazolo[3,2-a]pyrimidine derivatives based on a previously identified lead compound, and we evaluated their anti-inflammatory activities. Structure-activity relationship studies led to the discovery of two highly potent inhibitors. The two promising compounds were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner in mouse primary peritoneal macrophages (MPMs). Furthermore, administration of these compounds resulted in lung histopathological improvements and attenuated LPS-induced ALI in vivo. Taken together, these data indicate that these novel thiazolo[3,2-a]pyrimidine derivatives could be developed as candidate drugs for the treatment of ALI.

The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4. In this study, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations and umbrella sampling (US) simulations were carried out to reveal the principle of the binding preference of ponatinib and AZD4547 towards FGFR4/FGFR1. The results provided by MM/GBSA illustrate that ponatinib has similar binding affinities to FGFR4 and FGFR1, while AZD4547 has much stronger binding affinity to FGFR1 than to FGFR4. A comparison of the individual energy terms suggests that the selectivity of AZD4547 towards FGFR1 versus FGFR4 is primarily controlled by the variation of the van der Waals interactions. The US simulations reveal that the PMF profile of FGFR1/AZD4547 has more peaks and valleys compared with that of FGFR4/AZD4547, suggesting that the dissociation process of AZD4547 from FGFR1 are easily trapped into local minima. Moreover, it is observed that FGFR1/AZD4547 has much higher PMF depth than FGFR4/AZD4547, implying that it is more difficult for AZD4547 to escape from FGFR1 than from FGFR4. The physical principles provided by this study extend our understanding of the binding mechanisms and provide valuable guidance for the rational design of FGFR isoform selective inhibitors.

This study investigates the relationships among product/process modularity, organizational learning practices, and mass customization (MC) capability. Drawing on organizational learning theory, we propose that organizational learning practices help to embed the knowledge gained from modular design practices into organizational processes, enhancing MC capability. We empirically test the mediating effects of two organizational learning practices—customization knowledge utilization and business process improvement—on the relationship between product/process modularity and MC capability, using data collected from Chinese manufacturers. We find strong support for the mediating role of organizational learning practices in the relationship between modularity and MC capability. Our findings have implications for management strategies and point to directions for further research in this area.

A focal length measurement method by fiber point-diffraction longitudinal interferometry is proposed. By applying two different longitudinal displacements for the object point respectively and measuring the corresponding displacements of the image point, the lens focal length is derived by Newton formula. The displacements of the object point are introduced by glass plates with known refractive index and thickness. The corresponding displacements of the image point are measured interfeorometrically based on the modeling of the longitudinal interferometry of two point sources. Experiments and error analysis reveal that this method has an accuracy less than 0.15% under normal laboratory environment.

Highlights • LX4 is one the most important genotypes of infectious bronchitis coronavirus worldwide. • Two LX4 genotype viruses have novel genomic organizations which lacked 3a and 5b gene, respectively. • Recombination events may be responsible for the emergence of the LX4 genotype. • Most of these viruses disappeared likely because they were not “fit” to adaptation in chickens. • The “fit” viruses continued to evolve and have become widespread and predominant in commercial poultry., We investigated the genomic characteristics of 110 LX4 genotype strains of infectious bronchitis viruses (IBVs) isolated between 1995 and 2005 in China. The genome of these IBVs varies in size from 27596 bp to 27790 bp. Most IBV strains have the typical genomic organization of other gamacoronaviruses, however, two strains lacked 3a and 5b genes as a result of a nucleotide change within the start codon in the 3a or 5b genes. Analysis of our 110 viruses revealed that recombination events may be responsible for the emergence of the LX4 genotype with different topologies. Most of these viruses disappeared (before mid-2005) because they were not “fit” to adaptation in chickens. Finally, those of the “fit” viruses (after mid-2005) continued to evolve and have become widespread and predominant in commercial poultry. In addition, few of these viruses experienced recombination with those of the vaccine strains at the 3′ end of the genome.

Head and neck cancer is the sixth most common cancer worldwide. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, exhibits a wide range of biological roles including a highly efficient and specific anti-tumor activity. Here, we aimed to examine the effect of DHA on head and neck carcinoma cells and elucidate the potential mechanisms. We used five head and neck carcinoma cell lines and two non-tumorigenic normal epithelial cell lines to achieve our goals. Cells were exposed to DHA and subjected to cellular activity assays including viability, cell cycle analysis, cell death, and angiogenic phenotype. Our results show that DHA causes cell cycle arrest which is mediated through Forkhead box protein M1 (FOXM1). We also demonstrate that DHA induces ferroptosis and apoptosis in head and neck carcinoma cells. Lastly, our results show that DHA alters the angiogenic phenotype of cancer cells by reducing the expression of angiogenic factors and the ability of cancer cells to support endothelial cell tubule formation. Our study suggests that DHA specifically causes head and neck cancer cell death through contribution from both ferroptosis and apoptosis. DHA may represent an effective strategy in head and neck cancer treatment.

Yeasts and filamentous fungi do not have adenosine deaminase acting on RNA (ADAR) orthologs and are believed to lack A-to-I RNA editing, which is the most prevalent editing of mRNA in animals. However, during this study with the PUK1 (FGRRES_01058) pseudokinase gene important for sexual reproduction in Fusarium graminearum, we found that two tandem stop codons, UA1831GUA1834G, in its kinase domain were changed to UG1831GUG1834G by RNA editing in perithecia. To confirm A-to-I editing of PUK1 transcripts, strand-specific RNA-seq data were generated with RNA isolated from conidia, hyphae, and perithecia. PUK1 was almost specifically expressed in perithecia, and 90% of transcripts were edited to UG1831GUG1834G. Genome-wide analysis identified 26,056 perithecium-specific A-to-I editing sites. Unlike those in animals, 70.5% of A-to-I editing sites in F. graminearum occur in coding regions, and more than two-thirds of them result in amino acid changes, including editing of 69 PUK1-like pseudogenes with stop codons in ORFs. PUK1 orthologs and other pseudogenes also displayed stage-specific expression and editing in Neurospora crassa and F. verticillioides. Furthermore, F. graminearum differs from animals in the sequence preference and structure selectivity of A-to-I editing sites. Whereas A's embedded in RNA stems are targeted by ADARs, RNA editing in F. graminearum preferentially targets A's in hairpin loops, which is similar to the anticodon loop of tRNA targeted by adenosine deaminases acting on tRNA (ADATs). Overall, our results showed that A-to-I RNA editing occurs specifically during sexual reproduction and mainly in the coding regions in filamentous ascomycetes, involving adenosine deamination mechanisms distinct from metazoan ADARs.

We demonstrate that the key target of increased PIP3 on cell polarity and migration is the excessive Akt signaling. In Dictyostelium, the defects in cells lacking PTEN are suppressed by the secondary deletions of PkbA, or its activator, TorC2. Multiple novel PkbA substrates are identified, and one of them, PakA, links PIP3 to downstream signaling., By limiting phosphotidylinositol 3,4,5-triphosphate (PIP3) levels, tumor suppressor PTEN not only controls cell growth but also maintains cell polarity required for cytokinesis and chemotaxis. To identify the critical targets of PIP3 that link it to the cytoskeleton, we deleted secondary genes to reverse the deficiencies of pten- cells in Dictyostelium. The polarity defects in pten- cells correlate with elevated phosphorylations of PKB substrates. Deletion of AKT orthologue, PkbA, or a subunit of its activator TORC2, reduced the phosphorylations and suppressed the cytokinesis and chemotaxis defects in pten- cells. In these double mutants, the excessive PIP3 levels and, presumably, activation of other PIP3-binding proteins had little or no effect on the cytoskeleton. In bands with increased phosphorylation in pten- cells, we found PKB substrates, PI5K, GefS, GacG, and PakA. Disruption of PakA in pten- cells restored a large fraction of the cells to normal behavior. Consistently, expression of phosphomimetic PakA in pten- cells exacerbated the defects but nonphosphorylatable PakA had no effect. Thus, among many putative PTEN- and PIP3-dependent events, phosphorylation of PKB substrates is the key downstream regulator of cell polarity.

A novel method that could experimentally trace the ray propagation of an optical system based on point diffraction interferometry (PDI) is presented. The ray represented by the line connecting two point light sources (PLS) intersects with two parallel photographic planes, which are separated at a distance. The intersections of the ray defined by the PLSs with the planes occur where the optical path difference is a maximum and can be determined from interferograms on the photographic planes. The ray is determined by connecting the two intersections. Using fibers as the PLSs and CCD arrays as the photographic planes, we demonstrate its principle and its application in focal length measurement through experiments.

Compared to other approaches to improving digital image correlation (DIC) measurement accuracy, improving image quality is becoming increasingly effective. Image noise level, which is the main indicator of image quality, is very sensitive to the configurations of an imaging system and affects DIC measurement accuracy. However, the mechanism by which the imaging configurations affect accuracy is unclear. In this study, the influence of imaging configuration on DIC measurement accuracy was investigated using the common factor of noise. Firstly, the type and levels of noise introduced into actual images by different imaging system configurations were investigated. Next, the effect of noise on DIC measurement accuracy was determined using simulated images. Finally, the effects of imaging configuration on DIC measurement accuracy were experimentally investigated using actual measurements. The results show that both camera-related and lens-related configurations affect DIC measurement accuracy. In particular, lengthening the exposure time and reducing the f-number of the lens achieve similar improvement in DIC measurement accuracy, and a prime lens with high light transmittance is recommended for full-field optical measurements. In contrast, the imaging gain does not affect the accuracy of DIC measurements.

A fast signal-to-noise ratio (SNR) digital test method for a CCD camera is presented in this study. The proposed method employs the conventionally used differential operations of two sequential images to determine the noise. However, the technique focuses on two features to improve the SNR evaluation: the noise is separated from the differential image by a specially designed digital high-pass filter that does not affect the noise intensity; and the additional quantization noise introduced into the digital image by the frame grabber is corrected for in the final calculation. The method can produce an objective measurement that offers high repeatability. The results obtained are consistent with those produced by industry standard instruments.

Obesity is often associated with increased risk of cardiovascular diseases. Previous studies suggest that epidermal growth factor receptor (EGFR) antagonism may be effective for the treatment of angiotensin II-induced cardiac hypertrophy and diabetic cardiomyopathy. This study was performed to demonstrate if EGFR plays a role in the pathogenesis of hyperlipidemia/obesity-related cardiac injuries. The in vivo studies using both wild type (WT) and apolipoprotein E (ApoE) knockout mice fed with high fat diet (HFD) showed the beneficial effects of small-molecule EGFR inhibitors, AG1478 and 542, against obesity-induced myocardial injury. Administration of AG1478 and 542 significantly reduced myocardial inflammation, fibrosis, apoptosis and dysfunction in both two obese mouse models. In vitro, EGFR signaling was blocked by either siRNA silencing or small-molecule EGFR inhibitors in palmitic acid (PA)-stimulated cardiomyocytes. EGFR inhibition attenuated PA-induced inflammatory response and apoptosis in H9C2 cells. Furthermore, we found that PA-induced EGFR activation was mediated by the upstream TLR4 and c-Src. This study has confirmed the detrimental effect of EGFR activation in the pathogenesis of obesity-induced cardiac inflammatory injuries in experimental mice and has demonstrated the TLR4/c-Src-mediated mechanisms for PA-induced EGFR activation. Our data suggest that EGFR may be a therapeutic target for obesity-related cardiovascular diseases.

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) was reported in some leukemia, and inhibition of STAT3 can be the strategy for the leukemia treatment in clinic. In this study, we tested the anti-tumor effect of compound A13, a water-soluble analogue of curcumin, in vitro and in vivo. Herein, we show that A13 was able to reduce the viability of mastocytoma (P815 cells) and reticulum cell sarcoma (A20 cells) as measured by MTS assay. This effect was accompanied by a marked increase in the proportion of apoptotic cells as measured by flow cytometry. Furthermore, Western blot analysis suggested that the anti-leukemia effect of A13 was realized via STAT3 inhibition. In addition, systemic treatment with A13 in the A20-bearing mice for 60 days resulted in a significant improvement of survival rate and marked reduction of liver metastasis. In summary, our data show that the A13 treatment could effectively be applied to acute leukemia via inhibiting STAT3 signaling pathway.

A new laser differential reflection-confocal lens thickness measurement (DRCTM) method is proposed for the high-accuracy measurement of the lens thickness. DRCTM uses the test beam reflected from the lens first and last surface to determine the vertex positions of the two surfaces. Differential confocal technology is used to precisely identify the lens vertexes of the lens first and last surfaces, thereby enabling the precise measurement of the lens thickness. Compared with the existing measurement methods, DRCTM has high accuracy and strong anti-interference capability. Theoretical analysis and experimental results indicate that the DRCTM measurement error can be limited to 0.0015%.

Tags have been used in different social medias, such as Delicious, Flickr, LinkedIn and Weibo. In previous work, considerable efforts have been made to make use of tags without identification of their different types. In this study, we argue that tags in user profile indicate three different types of information, say the basics age, status, locality, etc, interests and specialty of a person. Based on this novel user tag taxonomy, we propose a tag classification approach in Weibo to conduct a clearer image of user profiles, which makes use of three categories of features: general statistics feature including user links with followers and followings, content feature and syntax feature. Furthermore, different from many previous studies on tag which concentrate on user specialties, such as expert finding, we find that valuable information can be discovered with the basics and interests user tags. We show some interesting findings in two scenarios, including user profiling with people come from different generations and area profiling with mass appeal, with large scale tag clustering and mining in over 6 million identical tags with 13 million users in Weibo data.

Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide-induced acute lung injury via anti-inflammatory actions. Thirty-three 4-amino quinazolin derivatives were synthesized and screened for anti-inflammatory activities in lipopolysaccharide-induced macrophages. The most potent four compounds, 6h, 6m, 6p, and 6q, were shown dose-dependent inhibition against lipopolysaccharide-induced TNF-α and IL-6 release. Then, the preliminary structure-activity relationship and quantitative structure-activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide-induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q, obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide-induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research.

Recently cloud computing has been increasingly gaining attention and spreading in various industries. This novel paradigm also has received significant research focus on the data security and privacy issues due to its outsourced nature. However, few of the research efforts have been focused on data mobility issues which existed intrinsically in highly complex and dynamic cloud services. To address this challenge, this paper discusses full mobility management of cloud data from two aspects: data mobility management and user mobility management. The work is based on our previously proposed active data-centric framework. Taking advantage of this framework, the active data can establish an active binding relationship with its user. Any data mobility-related behavior could inform to its bundled user instantly and safely. The paper also discusses user mobility management via the self-adaptable heterogeneous network handoff mechanism to ensure the ubiquitous informing service in the mobile cloud environment. The experimental outcomes demonstrate the feasibility, proactivity, and efficiency by the full mobility management scheme. © 2013 IEEE.

A non-immersive lens refractive index measurement method based on fiber point-diffraction longitudinal interferometry is presented. The lens imaging process is simplified to the single refraction of the back surface if the object point is located at the vertex of the front surface. The lens refractive index is derived through measuring its thickness, radius of curvature of the back surface, the distance between the object point and the image point. Experiments indicate its accuracy is better than 2.2 × 10⁻⁴. Since the front surface is excluded in the imaging process, even an aspherical lens could be accurately measured by this method.

Weitao Fu,1,* Lingfeng Chen,1,* Zhe Wang,1 Chengwei Zhao,1 Gaozhi Chen,1 Xing Liu,1 Yuanrong Dai,2 Yuepiao Cai,1 Chenglong Li,1,3 Jianmin Zhou,1 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Respiratory Medicine, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA *These authors contributed equally tothis work Abstract: It is recognized that myeloid differentiation protein 2 (MD-2), a coreceptor of toll-like receptor 4 (TLR4) for innate immunity, plays an essential role in activation of the lipopolysaccharide signaling pathway. MD-2 is known as a neoteric and suitable therapeutical target. Therefore, there is great interest in the development of a potent MD-2 inhibitor for anti-inflammatory therapeutics. Several studies have reported that xanthohumol (XN), an anti-inflammatory natural product from hops and beer, can block the TLR4 signaling by binding to MD-2 directly. However, the interaction between MD-2 and XN remains unknown. Herein, our work aims at characterizing interactions between MD-2 and XN. Using a combination of experimental and theoretical modeling analysis, we found that XN can embed into the hydrophobic pocket of MD-2 and form two stable hydrogen bonds with residues ARG-90 and TYR-102 of MD-2. Moreover, we confirmed that ARG-90 and TYR-102 were two necessary residues during the recognition process of XN binding to MD-2. Results from this study identified the atomic interactions between the MD-2 and XN, which will contribute to future structural design of novel MD-2-targeting molecules for the treatment of inflammatory diseases. Keywords: myeloid differentiation 2, xanthohumol, binding mode, inflammation, molecular dynamics simulation&nbsp

We propose a new, active scheme for fast and reliable detection of P2P malware by exploiting the enemies' strength against them. Our new scheme works in two phases: host-level dynamic binary analysis to automatically extract built-in remotely-accessible/controllable mechanisms (referred to as Malware Control Birthmarks or MCB) in P2P malware, followed by network-level informed probing for detection. Our new design demonstrates a novel combination of the strengths from both host-based and network-based approaches. Compared with existing detection solutions, it is fast, reliable, and scalable in its detection scope. Furthermore, it can be applicable to more than just P2P malware, more broadly any malware that opens a service port for network communications (e.g., many Trojans/backdoors). We develop a prototype system, PeerPress, and evaluate it on many representative real-world P2P malware (including Storm, Conficker, and more recent Sality). The results show that it can effectively detect the existence of malware when MCBs are extracted, and the detection occurs in an early stage during which other tools (e.g., BotHunter) typically do not have sufficient information to detect. We further discuss its limitations and implications, and we believe it is a great complement to existing passive detection solutions.

We describe a method to simultaneously measure thickness variation and refractive index homogeneity of 300 mm diameter silicon wafers using a wavelength-shifting Fizeau interferometer operating at 1550 nm. Only three measurements are required, corresponding to three different cavity configurations. A customized phase shifting algorithm is used to suppress several high order harmonics and minimize intensity sampling errors. The new method was tested with both silicon and fused silica wafers and measurement results proved to be highly repeatable. The reliability of the method was further verified by comparing the measured thickness variation of a 150 mm diameter wafer to a measurement of the wafer flatness after bonding the wafer to an optical flat.

In celebration of JIPB's 60(th) anniversary, this paper summarizes and reviews the development process of the journal. To start, we offer our heartfelt thanks to JIPB's pioneer Editors-in-Chief who helped get the journal off the ground and make it successful. Academic achievement is the soul of academic journals, and this paper summarizes JIPB's course of academic development by analyzing it in four stages: the first two stages are mostly qualitative analyses, and the latter two stages are dedicated to quantitative analyses. Most-cited papers were statistically analyzed. Improvements in editing, publication, distribution and online accessibility--which are detailed in this paper--contribute to JIPB's sustainable development. In addition, JIPB's evaluation index and awards are provided with accompanying pictures. At the end of the paper, JIPB's milestones are listed chronologically. We believe that JIPB's development, from a national journal to an international one, parallels the development of the Chinese plant sciences.

Adhesive and migratory behavior can be cell type, integrin, and substrate dependent. We have compared integrin and substrate differences using three integrin receptors: α5β1, α6β1, and αLβ2 expressed in a common cell type, CHO.B2 cells, which lack integrin α subunits, as well as in different cell types that express one or more of these integrins. We find that CHO.B2 cells expressing either α6β1 or αLβ2 integrins migrate and protrude faster and are more directionally persistent on laminin or ICAM-1, respectively, than CHO.B2 cells expressing α5β1 on fibronectin. Despite rapid adhesion maturation and the presence of large adhesions in both the α6β1- and αLβ2-expressing cells, they display robust tyrosine phosphorylation. In addition, whereas myosin II regulates adhesion maturation and turnover, protrusion rates, and polarity in cells migrating on fibronectin, surprisingly, it does not have comparable effects in cells expressing α6β1 or αLβ2. This apparent difference in the integration of myosin II activity, adhesion, and migration arises from alterations in the ligand-integrin-actin linkage (molecular clutch). The elongated adhesions in the protrusions of the α6β1-expressing cells on laminin or the αLβ2-expressing cells on ICAM-1 display a novel, rapid retrograde flux of integrin; this was largely absent in the large adhesions in protrusions of α5β1-expressing cells on fibronectin. Furthermore, the force these adhesions exert on the substrate in protrusive regions is reduced compared to similar regions in α5-expressing cells, and the adhesion strength is reduced. This suggests that intracellular forces are not efficiently transferred from actomyosin to the substratum due to altered adhesion strength, that is, avidity, affinity, or the ligand-integrin-actin interaction. Finally, we show that the migration of fast migrating leukocytes on fibronectin or ICAM-1 is also largely independent of myosin II; however, their adhesions are small and do not show retrograde fluxing suggesting other intrinsic factors determine their migration differences, ARH was supported by National Institutes of Health grants GM23244 and the Cell Migration Consortium (U54 GM064346). MVM is supported by the Ramon y Cajal program (RYC-2010-06094) from the Spanish Ministerio de Economía y Competividad (MINECO). PWW acknowledges funding support from the Natural Sciences and Engineering Council of Canada (NSERC) and the Canadian Institutes of Health Research. LPT acknowledges fellowship support from Fonds québécois de la recherche sur la nature et les technologies (FQRNT) and NSERC

Two-color spatio-temporal image cross-correlation spectroscopy (STICCS) is a new, to our knowledge, image analysis method that calculates space-time autocorrelation and cross-correlation functions from fluorescence intensity fluctuations. STICCS generates cellular flow and diffusion maps that reveal interactions and cotransport of two distinct molecular species labeled with different fluorophores. Here we use computer simulations to map the capabilities and limitations of STICCS for measurements in complex heterogeneous environments containing micro- and macrostructures. We then use STICCS to analyze the co-flux of adhesion components in migrating cells imaged using total internal reflection fluorescence microscopy. The data reveal a robust, time-dependent co-fluxing of certain integrins and paxillin in adhesions in protrusions when they pause, and in adhesions that are sliding and disassembling, demonstrating that the molecules in these adhesions move as a complex. In these regions, both α6β1- or αLβ2-integrins, expressed in CHO.B2 cells, co-flux with paxillin; an analogous cotransport was seen for α6β1-integrin and α-actinin in U2OS. This contrasts with the behavior of the α5β1-integrin and paxillin, which do not co-flux. Our results clearly show that integrins can move in complexes with adhesion proteins in protrusions that are retracting.

Modular design and modular process have been taken of granted as panacea for success of implementation of mass customization by numerous papers in the past two decades. However, based on literature review, this paper argued that it is the operations management practices of knowledge re-use and re-engineering that play an important role as mediator between modularity and mass customization capability, and the focus should shift from technical solutions of modularity to management practices. An empirical examination model was proposed for further testing of the hypothesis.

A new six-step phase shifting method is presented in this paper to determine the phase retardation for whole-field photoelastic stress analysis in optical glass based on the plane polariscope setup. This new phase stepping strategy is of no quarter wave plate errors and with less intensity variations of emerging light. By this method, it's not necessary to determine the isoclinic angles in advance when measuring the phase retardations, so the data processing will be simplified and the isoclinic angle errors will cause no influnces on the measurement. A plane polariscope is setup including a LED array light source, rotatable dichroic polymer film polarizer and analyser, a digital CCD camera and image grab system. Two mica waveplates with known phase retardances are measured, and the experimental results agree well with the those values. This method is expected to be used for the stress induced birefringence test in optical glass.