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The Mo 2 C@C catalyst was prepared by the calcination method under the argon gas flow of the activated walnut shell-ammonium heptamolybdate hybrid powder mixture, enhancing the electrocatalytic hydrogen evolution process. • The waste walnut shell powder was chosen as the carbon source for HER catalysts. • The walnut shell powders derived carbon matrix can enhance the electron transfer. • The open pores can facilitate electrolyte permeation and hydrogen release. Herein, we choose the waste walnut shell as the carbon source, and ammonium heptamolybdate as the molybdenum source to prepare the β-Mo 2 C catalyst supported on carbon matrix (Mo 2 C@C) by the calcination method for hydrogen evolution reaction (HER). The open pores in the porous Mo 2 C nanoparticle clusters can facilitate electrolyte permeation and hydrogen molecules release as well as the carbon matrix can enhance the conductivity. As a result, the optimal Mo 2 C exhibits an efficient HER performance, with an overpotential of 140 mV at 10 mA cm−2 and a Tafel slope of 63 mV dec−1 as well as excellent electrochemical stability. The strategy changing waste walnut shell into the effective catalysts sets an example for the searching and designing rational energy materials. [ABSTRACT FROM AUTHOR]

Currently, very limited information is available regarding the economic burdens of patients with extremity post-traumatic osteomyelitis (OM). This study aimed to investigate direct health care costs and utilization for inpatients with extremity post-traumatic OM and analyze its constituent ratios and influencing factors in Southern China. We searched in the electronic medical record system for inpatients who had received surgical interventions at our department between 2013 and 2016 for extremity post-traumatic OM. Data of direct health care costs incurred during their hospitalizations were collected in six main categories (service, diagnosis, treatment, materials, pharmaceuticals, and miscellaneous expenses). In addition, data of total medical costs for contemporaneous inpatients with non–post-traumatic OM were also collected as controls. A total of 278 post-traumatic OM and 10,420 controls were included. The median cost for the post-traumatic OM inpatients was $10,504 US dollars, 4.8-fold higher than that for those with non–post-traumatic OM ($2189, P < 0.001). The direct cost in the category of materials accounted for the largest proportion (61%), followed by that in pharmaceuticals (12%) and treatment (11%). The median number of hospital admissions for post-traumatic OM patients was 1 time, with a median length-of-stay of 22 d. The most influencing factors for the health care costs of the post-traumatic OM inpatients were use of an external fixator ($16,016 for those who used versus $4956 for those who did not, P < 0.001), external fixator type ($19,563 for ring fixator versus $14,966 for rail fixator, P < 0.001), infection site ($13,755 for tibia, $14,216 for femur and $5673 for calcaneus, P < 0.001), and infection-associated injury type ($12,890 for infection after open fracture versus $8087 for infection after closed fracture, P = 0.001). An unexpectedly large proportion of the direct health care costs for inpatients with extremity post-traumatic OM went to cover an external fixator, with expenses for pharmaceuticals and treatment accounting for only a little more than the tenth of the total health care costs. Use of external fixator, external fixator type, infection site, and infection-associated injury type directly influenced the health care costs. [ABSTRACT FROM AUTHOR]

A three-dimensional free-standing hard carbon (FHC) electrode is synthesized by carbonizing the hemp haulm and employed as anode for sodium-ion batteries directly. A high current charging-discharging process is carried out to reconstruct surface structure of the FHC. Surface reconstructed FHC display a high capacity of 256 mAh/g and enhanced rate ability. With the formation of order surface structure, the plateau capacity increase and more sodium ions can insert into the FHC. This work demonstrates the importance of surface structure for sodium ion diffusion and storage and provide a new strategy to design high-performance anode materials. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel KRASG12C inhibitors with 1-amino-3-aryl isoquinoline scaffold were designed using structure-based drug design. • A ruthenium-catalyzed direct mono C H functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was developed. • The target compounds 1-amino-3-aryl isoquinolines were facilely prepared using this new developed method. • Two compounds were identified with KRASG12C inhibitory activity. Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct mono C H functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity. [ABSTRACT FROM AUTHOR]

Abstract Aristaless-like homeobox1 (ALX1), a member of the ALX family, is capable of mediating survival and development of mesenchyme-derived elements in vertebrates and its mutation will prevent the fusion of frontonasal and maxillary elements. Recently, ALX1 has been reported to be associated with cancer progression. However, the specific roles of ALX1 in melanoma remain unclear. In this study, we investigated the expression pattern and biological functions of ALX1 in melanoma. We found that ALX1 was highly expressed in melanoma tissues and cell lines. Knockdown of ALX1 suppressed the proliferation and invasion of melanoma cells. Furthermore, we showed that ALX1 knockdown reversed the epithelial-mesenchymal transition (EMT) process in melanoma cells, which might be attributed to inactivation of the Wnt/β-catenin pathway. Taken together, this study provided a new insight into the role of ALX1 as a therapeutic target for melanoma treatment. Highlights • ALX1 is highly expressed in human melanoma tissues and cell lines. • Knockdown of ALX1 suppressed the proliferation and invasion of melanoma cells. • Knockdown of ALX1 reversed the EMT process in melanoma cells. • Knockdown of ALX1 inhibited the activity of Wnt/β-catenin pathway in melanoma cells. [ABSTRACT FROM AUTHOR]

Abstract Exposure to chronic stress can produce maladaptive neurobiological changes in pathways associated with pain processing, which may cause stress–induced hyperalgesia (SIH). However, the underlying mechanisms still remain largely unknown. In previous studies, we have reported that the amygdala is involved in chronic forced swim (FS) stress–induced depressive-like behaviors and the exacerbation of neuropathic pain in rats, of which, the basolateral amygdala (BLA) and the central nucleus of the amygdala (CeA) are shown to play important roles in the integration of affective and sensory information including nociception. Here, using in vivo multichannel recording from rostal anterior cingulate cortex (rACC) and BLA, we found that chronic FS stress (CFSS) could increase the pain sensitivity of rats in response to low intensity innoxious stimuli (LIS) and high intensity noxious stimuli (HNS) imposed upon the hindpaw, validating the occurrence of SIH in stressed rats. Moreover, we discovered that CFSS not only induced an increased activity of rACC neuronal population but also produced an augmented field potential power (FPP) of rACC local field potential (LFP), especially in low frequency theta band as well as in high frequency low gamma band ranges, both at the baseline state and under LIS and HNS conditions. In addition, by using a cross-correlation method and a partial directed coherence (PDC) algorithm to analyze the LFP oscillating activity in rACC and BLA, we demonstrated that CFSS could substantially promote the synchronization between rACC and BLA regions, and also enhanced the neural information flow from rACC to BLA. We conclude that exposure of chronic FS stress to rats could result in an increased activity of rACC neuronal population and promote the functional connectivity and the synchronization between rACC and BLA regions, and also enhance the pain–related neural information flow from rACC to BLA, which likely underlie the pathogenesis of SIH. Highlights • Chronic FS stress induces hyperalgesia and rACC neuron sensitization in rats. • Chronic FS stress increases rACC field potential power in theta and low gamma bands. • Chronic FS stress promotes synchronous activity between rACC and BLA regions. • Chronic FS stress enhances the neural information flow from rACC to BLA. • Sensitized rACC neurons and enhanced neural flow from rACC to BLA underlie SIH. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Unique nanostructure, high electrical conductivity, satisfactory energy density, and extraordinary cycling stability are important evaluation criteria for high-efficient energy storage devices. Herein, Fe 3 O 4 nanospheres are successfully in situ decorated on graphene nanosheets through an environmentally benign and facile solvothermal procedure. When utilized as an electrode for supercapacitor, the graphene/Fe 3 O 4 nanocomposite exhibits a notably enhanced specific capacity (268 F·g−1 at 2 mV·s−1) and remarkable cycling performance with 98.9% capacity retention after 10,000 cycles. Furthermore, the fabricated graphene/MnO 2 //graphene/Fe 3 O 4 asymmetric supercapacitor device displays a desirable energy density (87.6 Wh·kg−1) and superior cycling stability (93.1% capacity retention after 10,000 cycles). [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Flexible supercapacitor plays a progressively more important part in power source for smart electronic devices and how to enhance its energy density is the urgent issue to be addressed. Hence, a hybrid electrode of Polypyrrole@reduced graphene oxide hydrogel (PPy@rGOH) is synthesized via a combine hydrothermal treatment of GO solution to assemble hydrogel and subsequently in-situ electropolymerization preparation of PPy on the surface of graphene. Through controlling the time of electropolymerization, the resultant PPy@rGOH-20 s with high specific surface area exhibits an excellent specific capacitance of 340 F g−1 at a current density of 1 A g−1 and superior cycling stability of 87.4% capacitance retention after 10,000 charging/discharging cycles at 3 A g−1 in 1 M KNO 3. The assembled flexible asymmetric supercapacitor (FASC) by employing the PPy@rGOH-20s as positive electrode and pure rGOH as negative electrode presents a maximum operational voltage window of 1.6 V and high energy density of 46.9 W h kg−1, which is higher than polymer/carbon-based supercapacitors previously reported. [ABSTRACT FROM AUTHOR]

Architecture of electrode materials plays an important role in achieving favorable electrochemical performance via providing fast electronic transport pathway and shorten lithium ion diffusion distance. Herein, ultrafine CoP nanoparticles were successfully embedded in carbon nanorod, which were grown on the biomass-derived carbon (BC). When applied as anode materials for lithium-ion batteries, these CoP@C/BC displayed capable specific capacity, remarkable rate ability and outstanding long-term cycling performance. The capacity was governed by combination of diffusion-controlled and capacitive processes, according to quantitative kinetic analysis. The good electrochemical performance is attributed to hierarchical construction of nanosized CoP embedded in carbon nanorod and BC with high conductivity composite, which relieve the volume changing of CoP and provide large electrode/electrolyte interface. The present design of hierarchical architecture can be extended to other transition metal-based oxides, sulfide and phosphide electrode materials for high performance alkali metal ion batteries. [ABSTRACT FROM AUTHOR]

[Display omitted] • Natural rare bioactive myrsinane diterpene derivatives were prepared through a bioinspired skeleton conversion strategy from natural abundant lathyrane diterpene Euphorbia factor L 3. • 5-Ester group in myrsinane diterpenes is essential for anti-AD activity. • The promising synthesized myrsinane derivative 37 exhibits higher anti-AChE activity than tacrine and better neuroprotective activity than guanosine. A series of novel myrsinane-type Euphorbia diterpene derivatives (1 – 37) were synthesized from the abundant natural lathyrane-type Euphorbia factor L 3 , using a multi-step chemical process guided by a bioinspired skeleton conversion strategy, with the aim of discovering potential anti-Alzheimer's disease (AD) bioactive lead compounds. The synthesis process involved a concise reductive olefin coupling reaction through an intramolecular Michael addition with a free radical, followed by a visible-light-triggered regioselective cyclopropane ring-opening. The cholinesterase inhibitory and neuroprotective activities of the synthesized myrsinane derivatives were evaluated. Most of the compounds showed moderate to strong potency, highlighting the importance of ester groups in Euphorbia diterpene. In particular, derivative 37 displayed the most potent acetylcholinesterase (AChE) inhibition, with an IC 50 value of 8.3 μM, surpassing that of the positive control, tacrine. Additionally, 37 also showed excellent neuroprotective effect against H 2 O 2 -induced injury in SH-SY5Y cells, with a cell viability rate of 124.2% at 50 μM, which was significantly higher than that of the model group (viability rate 52.1%). Molecular docking, reactive oxygen species (ROS) analysis, immunofluorescence, and immunoblotting were performed to investigate the mechanism of action of myrsinane derivative 37. The results indicated that derivative 37 may be a promising myrsinane-type multi-functional lead compound for the treatment of Alzheimer's disease. Furthermore, a preliminary SAR analysis was performed to study the acetylcholinesterase inhibitory and neuroprotective activities of these diterpenes. [ABSTRACT FROM AUTHOR]

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) has been a major threat to global industrial pig farming ever since its emergence in the late 1980s. Identification of sustainable and effective control measures against PRRSV transmission is a pressing problem. The nucleocapsid (N) protein of PRRSV is specifically localized in the cytoplasm and nucleus of virus-infected cells which is important for PRRSV replication. In the current study, a new host restricted factor, Moloney leukemia virus 10-like protein (MOV10), was identified as an inhibitor of PRRSV replication. N protein levels and viral replication were significantly reduced in Marc-145 cells stably overexpressing MOV10 compared with those in wild-type Marc-145 cells. Adsorption experiments revealed that MOV10 did not affect the attachment and internalization of PRRSV. Co-immunoprecipitation and immunofluorescence co-localization analyses showed that MOV10 interacted and co-localized with the PRRSV N protein in the cytoplasm. Notably, MOV10 affected the distribution of N protein in the cytoplasm and nucleus, leading to the retention of N protein in the former. Taken together, these findings demonstrate for the first time that MOV10 inhibits PRRSV replication by restricting the nuclear import of N protein. These observations have great implications for the development of anti-PRRSV drugs and provide new insight into the role of N protein in PRRSV biology. Highlights • Porcine reproductive and respiratory syndrome (PRRS) affects industrial pig farming. • N protein is the main protein of PRRS virus (PRRSV) in infected cells which is important for PRRSV replication. • Moloney leukemia virus 10 protein (MOV10) is a new host restriction factor of PRRSV. • MOV10 interacts with PRRSV N protein and inhibits PRRSV replication in vitro. • MOV10 inhibits nuclear entry of N protein, thus impairing viral life cycle. [ABSTRACT FROM AUTHOR]

Resistance to benzimidazole fungicides in many phytopathogenic fungi is caused by specific point mutations in the β -tubulin gene ( β-tubulin ). However, the mutated locus and genotype of β-tubulin differ among phytopathogenic fungi. To validate the point mutation in Fusarium asiaticum β 2 -tubulin that confers resistance to carbendazim and to analyze the molecular interaction between carbendazim and F. asiaticum β 2 -tubulin. In this study, a new point mutation (GAG → GCG, E198A) at codon 198 of β 2 -tubulin in a wild-type F. asiaticum strain was constructed by site-directed mutagenesis followed by a split marker strategy. The site-directed mutants were verified and exhibited a high level of resistance to carbendazim. In the absence of fungicide treatment, the biological characteristics did not differ between the site-directed mutants and the wild-type strain. Molecular docking between carbendazim and β 2 -tubulin was carried out using the Surflex-Dock program in Sybyl X-2.0 version and the results indicated that the E198A mutation altered the configuration of β 2 -tubulin, resulting in the change of the bonding sites and docking scores. We concluded that the point mutation of F. asiaticum β 2 -tubulin conferring carbendazim resistance may not always be the bonding site for carbendazim. [ABSTRACT FROM AUTHOR]

Lecanicillium attenuatum is an important nematophagous fungus with potential as a biopesticide for control of plant-pathogenic nematodes. However, relatively low fungicide-tolerance limits its application in the field. To improve the propamocarb-tolerance of L. attenuatum , a low-energy N + ion implantation-based mutagenesis system was established. In the first round of N + ion implantation, a proper conidial lethality rate (87.2–88.8%) and the highest positive mutation rate (11.2–11.4%) were achieved, and the highest propamocarb-tolerant mutant LA-I-R1-T7-M1 and LA-I-R1-T7-M2 were isolated in the experiment 1 and experiment 2 respectively, having a median effective concentration (EC 50 ) value of 1223.6 and 1173.6 μg/ml respectively. Multiple rounds of N + ion implantation were further employed, but fungal propamocarb-tolerance had not been significantly enhanced until the fifth-round of ion implantation. The LA-I-R5-M1 was the highest tolerant to propamocarb among all the mutants, whose EC 50 value was increased 2.54-fold compared to wild-type strain, reaching to the 1298.7 μg/ml. Its EC 50 value was significantly increased with continuous passaging, which was stable from the fifth- to fifteenth-generation, and then declined. However the EC 50 value of the twentieth-generation strain was still higher than the EC 50 (1298.7 μg/ml) of the first-generation strain. The colony growth, conidia yield and conidial germination of mutants on plates, and their parasitism in the nematode eggs of Meloidogyne incognita and Heterodera glycines were not significantly changed in both single- and multiple-round of N + ion implantation. In conclusion, we had succeeded in improving the propamocarb-tolerance of L. attenuatum through this low-energy N + ion implantation-based mutagenesis system. The improved strain LA-I-R5-M1 could be potentially applied in combination with propamocarb in the field. [ABSTRACT FROM AUTHOR]

Objective To establish a high throughput, low cost, and simple nanotechnology-based method for the detection of single nucleotide polymorphism (SNP) loci in type 2 diabetes mellitus (T2DM). Methods Multiplex ligase detection reaction (LDR) amplification was performed using fluorescently labeled magnetic nanosphere-bound upstream LDR probes and downstream probes labeled with a unique fluorescent group for each SNP locus. The amplified LDR products were separated by magnetic nanospheres and then scanned by fluorescence spectroscopy. Four SNP loci associated with T2DM were detected, including the rs13866634 locus in SLC30A8, rs10811661in CDKN2A/2B, rs1111875 in the HHEX gene, and rs7903146 in the TCF7L2 gene. The SNP genotype was also determined by DNA sequencing as a control. Results The SNP genotypes of the four gene loci determined by the nanosphere-based multiplex LDR method were consistent with the DNA sequencing results. The accuracy rate was 100%. Conclusion A method based on multiplex PCR and LDR was established for simultaneous detection of four SNP loci of T2DM susceptibility genes. [ABSTRACT FROM AUTHOR]

• Long photoperiod failed to affect AS-stimulated fear response in zebrafish. • Short photoperiod alleviated AS-stimulated fear response in zebrafish. • Short photoperiod alleviated fear response through MT/5-HT/DA pathways and HPI axis. Photoperiod has been well-documented to be involved in regulating many activities of animals. However, whether photoperiod takes part in mood control, such as fear response in fish and the underlying mode(s) of action remain unclear. In this study, adult zebrafish males and females (Danio rerio) were exposed to different photoperiods, Blank (12 h light: 12 h dark), Control (12 h light: 12 h dark), Short daylight (SD, 6 h light: 18 h dark) and Long daylight (LD, 18 h light: 6 h dark) for 28 days. After exposure, fear response of the fish was investigated using a novel tank diving test. After alarm substance administration, the onset to higher half, total duration in lower half and duration of freezing in SD-fish were significantly decreased, suggesting that short daylight photoperiod is capable of alleviating fear response in zebrafish. In contrast, comparing with the Control, LD didn't show significant effect on fear response of the fish. Further investigation revealed that SD increased the levels of melatonin (MT), serotonin (5-HT) and dopamine (DA) in the brain while decreased the plasma level of cortisol comparing to the Control. Moreover, the expressions of genes in MT, 5-HT and DA pathways and HPI axis were also altered consistently. Our data indicated that short daylight photoperiod might alleviate fear response of zebrafish probably through interfering with MT/5-HT/DA pathways and HPI axis. [ABSTRACT FROM AUTHOR]

Lecanicillium attenuatum is an important nematophagous fungus with potential as a biopesticide for control of plant-pathogenic nematodes. However, relatively low fungicide-tolerance limits its application in the field. To improve the propamocarb-tolerance of L. attenuatum , a NTG-based mutagenesis system was established. Among different combinations of NTG concentration and treatment time in the first-round NTG treatment, the treatment of 1.0 mg/ml NTG for 60 min gave a proper conidial lethality rate of 84.6% and the highest positive mutation rate of 7.7%, and then produced the highest propamocarb-tolerant mutant LA-C-R1-T4-M whose EC 50 value reached to 1050.0 μg/ml. The positive mutation range was 105.1% in the first-round NTG treatment. Multiple-round NTG treatment was further employed to enhance the propamocarb tolerance of L. attenuatum . The positive mutation range was significantly accumulated to 179.3% on the third-round NTG treatment, and then appeared to level-off and remained constant. These results indicated that multiple-round NTG treatment had a significant accumulative effect on fungal tolerance to propamocarb. Among all chemical-mutants, the LA-C-R3-M was the highest tolerant to propamocarb, whose EC 50 value was increased 2.79-fold compared to the wild-type strain, and it was mitotic stable after 20 passages on PDA medium. Colony growth, conidia yield and conidial germination on plates, and parasitism of nematode eggs of M. incognita and H. glycines were not significantly changed by the NTG-based mutagenesis compared to the wild-type strain in either single- or multiple-round NTG treatment. In conclusion, we succeeded in improving the propamocarb tolerance of L. attenuatum via the optimized NTG-based mutagenesis system. The improved strain LA-C-R3-M could be potentially applied with propamocarb in the field. [ABSTRACT FROM AUTHOR]

Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using 13 C 6 -glucose, 13 C-1+2-glucose, 13 C 5 , 15 N 2 -Gln, 13 C 3 -glycerol, and 13 C 8 -octanoate as tracers. These tracers were designed to probe the central energy producing and anabolic pathways (glycolysis, pentose phosphate pathway, Krebs Cycle, glutaminolysis, nucleotide synthesis and lipid turnover). We found that glycolysis was not associated with the rate of breast cancer cell proliferation, glutaminolysis did not support lipid synthesis in primary breast or breast cancer cells, but was a major contributor to pyrimidine ring synthesis in all cell types; anaplerotic pyruvate carboxylation was activated in breast cancer versus primary cells. We also found that glucose metabolism in individual breast cancer cell lines differed between in vitro cultures and tumor xenografts, but not the metabolic distinctions between cell lines, which may reflect the influence of tumor architecture/microenvironment. [ABSTRACT FROM AUTHOR]

Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. [ABSTRACT FROM AUTHOR]

[Display omitted] Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe2+- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy. [ABSTRACT FROM AUTHOR]

Rosabanksiae is a vine-like shrub rose that is endemic to China. In recent years, leaf spot disease hasbeen observed frequently in park in Nanjing City, Jiangsu Province, China. The initial symptoms were small yellow spots; as the disease progressed, the lesions became dark brown. Isolates NLXH2-1-1, NLXH2-2-3, and NLXH 2-4-3 were obtained. Koch's postulates were tested and confirmed that these isolates were pathogenic. Morphologically, macroconidia were cylindrical, rounded at both ends, straight, and (48–) 50–55 (−60) × (2.5–) 3.5–4.5 (−5) μm in length (av. = 52.5 × 4 μm), with 1–3-septate, and gathered conidia bundles. By morphological features and multigene phylogenetic analysis of the six genesITS, act, cmdA, his, LSU and tub2 region, the causal fungus is Calonectria fujianensis.This is the first report leaf spot by Ca. fujianensis on the R. banksiae, provide a theoretical basis for disease prevention and control. • By pathogenicity, morphological, multigene phylogenetic analysis the causal of leaf spot on R. banksiae is Ca. fujianensis. [ABSTRACT FROM AUTHOR]

Genetic interactions play critical roles in genotype-phenotype associations. We developed a novel interaction-integrated linear mixed model (ILMM) that integrates a priori knowledge into linear mixed models. ILMM enables statistical integration of genetic interactions upfront and overcomes the problems of searching for combinations. To demonstrate its utility, with 3D genomic interactions (assessed by Hi-C experiments) as a priori, we applied ILMM to whole-genome sequencing data for Autism Spectrum Disorders (ASD) and brain transcriptome data, revealing the 3D-genetic basis of ASD and 3D-expression quantitative loci (3D-eQTLs) for brain tissues. Notably, we reported a potential mechanism involving distal regulation between FOXP2 and DNMT3A , conferring the risk of ASD. • A novel linear mixed model (ILMM) integrates a priori knowledge of genetic interactions. • ILMM reduces the risk of overfitting and the burden of multiple-test corrections. • ILMM quantifies the strength of genotype-phenotype associations in interacting genetic regions. • ILMM reveals a promising distal regulation mechanism between FOXP2 and DNMT3A in ASD. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of lathyrane-type Euphorbia diterpene derivatives featured unique 3 R configuration were synthesized based on the configuration inversion strategy. • Most synthesized compounds were exhibited the moderate or strong potency for antiproliferation activity and MDR reversal ability. • Compounds 21 and 25 had excellent cytotoxicity against MCF-7, 4 T1 and HepG2 cells. • Compound 25 also showed potential MDR reversal ability with the reversal fold of 16.1 higher than that of positive control verapamil. A series of lathyrane-type Euphorbia diterpene derivatives featured 3 R configuration (H-3 β) were synthesized from natural rich Euphorbia factor L 3 via modified Mitsunobu reaction based on configuration inversion strategy. The antiproliferation activity and MDR reversal ability of the lathyrane derivatives were evaluated, and the most synthesized compounds showed moderate or strong potencies. Among them, diterpenes 21 (IC 50 values of 2.6, 5.2 and 13.1 μM, respectively) and 25 (IC 50 values of 5.5, 8.6 and 1.3 μM, respectively) presented the strong cytotoxicity against MCF-7, 4 T1 and HepG2 cells. Meanwhile, derivative 25 exhibited excellent MDR reversal ability with the reversal fold of 16.1 higher than that of verapamil. The cellular thermal shift assay and molecular docking proved direct engagement of diterpene 25 to ABCB1, suggesting 25 could be a promising MDR modulator. Furthermore, the preliminary SARs of these diterpenes were also discussed. [ABSTRACT FROM AUTHOR]

Defective DNA repair has been linked with age-associated neurodegenerative disorders. Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Whether damages to nuclear DNA contribute to neurodegeneration of PD still remain obscure. in this study we aim to explore whether nuclear DNA damage induce dopamine neuron degeneration in A53T human α-Synuclein over expressed mouse model. We investigated the effects of X-ray irradiation on A53T-α-Syn MEFs and A53T-α-Syn transgene mice. Our results indicate that A53T-α-Syn MEFs show a prolonged DNA damage repair process and senescense phenotype. DNA damage preceded onset of motor phenotype in A53T-α-Syn transgenic mice and decrease the number of nigrostriatal dopaminergic neurons. Neurons of A53T-α-Syn transgenic mice are more fragile to DNA damages. [ABSTRACT FROM AUTHOR]

This paper is devoted to the study of the convergence of the Lax–Oleinik semigroup associated with reversible Hamiltonians H ( x , p ) on R n . We provide a necessary and sufficient condition for the convergence of the semigroup. We also give an example to show that for irreversible Hamiltonians on R n , even if the Hamiltonian is integrable and the initial data is Lipschitz continuous and bounded, the corresponding Lax–Oleinik semigroup may not converge. [ABSTRACT FROM AUTHOR]

Diniconazole and hexaconazole are wide spectrum triazole fungicides with high-efficiency and low toxicity. The specific molar heat capacity ( C p ,m ) of diniconazole and hexaconazole were determined by a continuous C p mode of micro-calorimeter and theoretical calculation, their C p ,m values at T = 298.15 K were 381.72 J K −1 mol −1 and 364.66 J K −1 mol −1 , respectively. The C p ,m value of diniconazole is higher than that of hexaconazole at temperature from T = (283.15 to 353.15) K. [ABSTRACT FROM AUTHOR]

The cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) have been implicated as important mediators of the inflammatory reaction in patients with intestinal inflammation. The present study was designed to investigate the roles of these cytokines on mucosal barrier function in a mouse model of acute colitis with using anti-cytokine strategies. Mice received 3% dextran sulfate sodium (DSS) in their drinking water for 7 days showed morphological alteration of mucosa and increase of intestinal permeability. Administration of IL-6 monoclonal antibody (mAb) or TNF-α mAb significantly attenuated intestinal permeability. IL-6 mAb and TNF-α mAb treatment also effectively suppressed the expression of claudin-2 and myosin light chain kinase (MLCK). Taken together, we indicated that anti-IL-6 and anti-TNF-α therapy prevent intestinal permeability induced by intestinal inflammation. [ABSTRACT FROM AUTHOR]

Diploid and tetraploid Jiaogulan ( Gynostemma pentaphyllum ) seeds were examined for their conjugated linolenic acids and nutraceutical components. Both di- and tetraploid Jiaogulan seeds were rich in conjugated linolenic acids possibly including α-eleostearic, catalpic and β-eleostearic acids for about 80% of total fatty acids. α-Eleostearic acid was the primary conjugated isomer at a level of 98.8 and 187.7 mg/g dried seeds in diploid and tetraploid seeds, respectively. The seeds also contained significant levels of essential amino acids (616.3 and 541.5 μmol/g dry seeds), phytosterols (1292.0 and 2316.0 μmol/kg dry seeds), tocopherols, phenolics and flavonoids. In addition, the seeds extract showed no difference in their anti-inflammatory effects in LPS-stimulated RAW 264.7 mouse macrophage cells, whereas the diploid seed extract had stronger radical scavenging activities and a ferric reducing capability than those of the tetraploid seed extract on a per seed weight basis. The results may be used to promote the value-added utilization of Jiaogulan seeds. [ABSTRACT FROM AUTHOR]

The inflammatory response is one of the first defenses our body has to fight against potential endangerments. It plays a critical role in host defense, clearing and slowing the infection in the case of microbial invasion. During an inflammatory response, a variety of cytokines are produced by cells and trigger or enhance the specific inflammation response. TNFα, one of these factors, plays a crucial role in many immune and inflammatory processes, such as proliferation, apoptosis, necrosis, and cell survival. It acts in orchestrating the cytokine cascade and the major regulator of inflammatory cytokine production. Abnormality of TNFα signaling leads to many diseases, including rheumatoid arthritis, psoriasis, Crohn's disease, atherosclerosis, and cancer. Due to the importance of TNFα, regulating TNFα activity is a key to treat the related diseases. There is a long history of using medicinal herbs to treat diseases related to inflammation. We searched for an ingredient that has the ability to inhibit TNFα, we examined AO herbal extract, containing 10 individual herbs and most of these herbs have anti-inflammatory activity within humans. We have tested the anti-inflammatory ability of AO herbal extract on mice. Furthermore, we used macrophage cell from young mice and found that AO extract has the ability to reduce the inflammation by inhibiting TNFα level. [ABSTRACT FROM AUTHOR]

IKKε is an IκB kinase functioning in NF-κB signal pathway in the innate immune system of higher vertebrates. To exploit the function of IKKε of black carp (bcIKKε) in its antiviral innate immunity, the IKKε gene has been cloned from the RNA isolated from the spleen of black carp. The full-length cDNA of bcIKKε is 2537 bp, which encodes the peptide of 723 amino acids. bcIKKε contains a S-Tkc domain, a PKc domain and a UBL-TBK1-like domain and bcIKKε shares the highest amino acid sequence similarity with that of grass carp. bcIKKε was constitutively transcribed in the selected tissues of black carp including gill, kidney, heart, intestine, liver, muscle, skin and spleen; and the mRNA level of bcIKKε in these tissues varied right after SVCV or GCRV infection. bcIKKε had been well expressed in HEK293T cells and western blot assay determined that this fish kinase was around 80 KDa. The immunofluorescence assay of both NH3T3 cells and EPC cells demonstrated that bcIKKε was located in the cytosolic part of the cell. Report assay result showed that overexpression of bcIKKε in EPC cells activated the expression of both zebrafish IFN and EPC IFN. All our data suggest that bcIKKε is a novel fish kinase functioning in the innate antiviral immune response of black carp. [ABSTRACT FROM AUTHOR]

IKKε is an IKK-related kinase implicated in antiviral immune response in higher vertebrates. To elucidate the function of IKKε in teleost fish, grass carp IKKε (gcIKKε) has been cloned and characterized in this paper. The full-length cDNA of gcIKKε is composed of 2529 nucleotides and encodes a polypeptide of 723 amino acids. The mRNA transcription of gcIKKε was constitutively detected in all the selected tissues and the gcIKKε mRNA level increased at 36 h after GCRV infection. Western blot data of both HEK293T cells and EPC cells demonstrated that gcIKKε was around 80 KDa; and immunofluorescence staining data of both NIH3T3 cells and EPC cells determined gcIKKε was a cytosolic protein. The mRNA level of gcIKKε in CIK cells was increased more than 150 times right after poly(I:C) treatment and PMA treatment triggered gcIKKε mRNA transcription in CIK cells more than 100 times. Over-expression of gcIKKε in EPC cells activated the promoter activity of both zebrafish IFN and fathead minnow IFN. gcIKKε mRNA transcription level in CIK cells was increased from 48 h post GCRV infection with different MOIs. All the data support the idea that gcIKKε is a novel teleost IκB kinase recruited in the IFN-mediated antiviral immunity of grass carp. [ABSTRACT FROM AUTHOR]

Existing studies reported higher altitudes reduce the COVID-19 infection rate in the United States, Colombia, and Peru. However, the underlying reasons for this phenomenon remain unclear. In this study, regression analysis and mediating effect model were used in a combination to explore the altitudes relation with the pattern of transmission under their correlation factors. The preliminary linear regression analysis indicated a negative correlation between altitudes and COVID-19 infection in China. In contrast to environmental factors from low-altitude regions (<1500 m), high-altitude regions (>1500 m) exhibited lower PM2.5, average temperature (AT), and mobility, accompanied by high SO 2 and absolute humidity (AH). Non-linear regression analysis further revealed that COVID-19 confirmed cases had a positive correlation with mobility, AH, and AT, whereas negatively correlated with SO 2 , CO, and DTR. Subsequent mediating effect model with altitude-correlated factors, such as mobility, AT, AH, DTR and SO 2 , suffice to discriminate the COVID-19 infection rate between low- and high-altitude regions. The mentioned evidence advance our understanding of the altitude-mediated COVID-19 transmission mechanism. [Display omitted] • High altitudes reduce the COVID-19 infection. • Altitude changes the levels of MSI, DTR, AH, AT, and SO 2. • Multiple mediating model confirmed altitude-dependent COVID-19 infection. [ABSTRACT FROM AUTHOR]

A modified sodium bentonite geosynthetic clay liner (GCL) designed for acid-and-alkaline resistance was evaluated for its potential application in the containment of bauxite residue leachate. A modified fluid loss test was employed to quickly evaluate the hydraulic conductivity (k) of the GCL using distilled water, tap water, and four bauxite liquors (BLs, leachate from bauxite residue reservoirs). The effects of swelling capacity of bentonite, prehydration, hydraulic gradient (i), ionic strength (I), and relative abundance of monovalent and multivalent cations (RMD) on the hydraulic conductivity of the GCL were analyzed. The results indicated that the BLs significantly decreased free swell index of the bentonite. As compared to increasing i , prehydration obviously enhanced hydraulic performance of the GCL. The four BLs increased k of the GCL by a factor of 4–12 relative to the tap water permeation condition, and the resultant k exceeded upper limit of 5.0 × 10−11 m/s for GCLs. The increase in k was attributed to compression in diffuse double layer of the bentonite and dissolution in clay minerals in ion-rich and hyperalkaline BLs, manifesting that further modification on the GCL is needed. The I was found a better indicator than the RMD on correlation with chemical compatibility of the GCL. • Bauxite liquors deteriorated swelling capacity and permeability of the GCL. • Diffuse double layer compression and clay mineral dissolution caused chemical incompatibility. • Prehydration and high hydraulic gradient contributed to reduce hydraulic conductivity. • Ionic strength was the superior factor influenced hydraulic conductivity of GCL. [ABSTRACT FROM AUTHOR]

Type I interferons (IFNs) play an important role in the antiviral immune response in teleost fish. In this study, one type I interferon (bcIFNa) of black carp ( Mylopharyngodon piceus ) has been cloned and characterized. The full-length cDNA of bcIFNa gene consists of 783 nucleotides and the predicted bcIFNa protein contains 185 amino acids. Semi-quantitative RT-PCR analysis demonstrated that bcIFNa mRNA transcription level in all the selected tissues of black carp was greatly increased at 33 h post spring viremia of carp virus (SVCV) infection. The protein of bcIFNa could be detected in both the whole cell lysate and the supernatant media of HEK293T cells transfected with plasmids expressing bcIFNa through immunoblot assay. EPC cells showed greatly increased antiviral ability when the cells were treated with the bcIFNa-containing conditioned media for 24 h before SVCV infection. Mass spectrum assay and glycosidase digestion analysis determined that bcIFNa is modified with N-linked glycosylation, which occurs on the Asn (N) of 38 site of this cytokine. The un-glycosylated mutant bcIFNa-N38Q could be secreted out of the cell and showed the similar antiviral ability against SVCV as that of wild type bcIFNa, which suggested that N-linked glycosylation does not contribute directly to the antiviral property of this fish cytokine. [ABSTRACT FROM AUTHOR]

Recently pseudorabies outbreaks have occurred in many vaccinated farms in China. To identify genetic characteristics of pseudorabies virus (PRV) strains, we obtained the genomic sequences of PRV strains HeN1 and JS, which were compared to 4 PRV genomes and 729 partial gene sequences. PRV strains isolated in China showed marked sequence divergence compared to European and American strains. Phylogenetic analysis revealed that for the first time PRV can be divided into 2 distinct clusters, with Chinese strains being genotype II and PRVs isolated from other countries being genotype I. Restriction fragment length polymorphism analysis confirmed differences between HeN1 and Bartha strains, as did the presence of unique insertion/deletion polymorphisms and microsatellites. This divergence between the two genotypes may have been generated from long-term, independent evolution, which could also explain the low efficacy of the Bartha vaccine in protecting pigs infected with genotype II PRV. [ABSTRACT FROM AUTHOR]

Background The controversial results from different studies suggested that leukocyte recruitment mediated by leukotriene B4 (LTB4) and its receptor might improve pathogen clearance, but might also aggravate organ injury during sepsis. The present study was performed to compare the effect of BLT1 ligand LTB4 and its antagonist U-75302 on the development of sepsis. Methods Sepsis in mice was induced by cecal ligation and puncture (CLP). The mice were allocated into sham group, CLP group, U-75302 group, and LTB4 group. In the latter three groups, CLP mice were treated by intraperitoneal saline, U-75302, and LTB4, respectively. Their effect on the progression of sepsis were compared by histopathologic tests, level of systemic cytokines, counts of immune cells and bacterial clearance, and survival rate. Results The histopathologic tests showed that U-75302 attenuated lung injury, whereas LTB4 aggravated liver injury. LTB4 increased the plasma levels of interleukin-6, tumor necrosis factor-α, and U-75302 increased the level of plasma interleukin-10. LTB4 increased whereas U-75302 reduced the neutrophil numbers in the peritoneal lavage fluid. LTB4 also increased the number of peritoneal and splenic CD4+ and CD8+ T cells. Bacterial clearance in blood and peritoneal lavage fluid was significantly enhanced in the LTB4 group. Both U-75302 and LTB4 did not change the survival rate significantly compared with vehicle, but mortality in the LTB4 group was significantly higher than in the U-75302 group. Dose response analyses were also performed to compare the effect of U-75302 and LTB4 at different doses. Different doses of both agents did not influence the survival rate of CLP mice. Conclusions U-75302 attenuates sepsis-induced organ injury, whereas LTB4 increases the leukocyte recruitment toward infection site, but LTB4 showed a more lethal effect than U-75302 during polymicrobial sepsis. [ABSTRACT FROM AUTHOR]

Background Neighborhood built environment may influence residents' physical activity, which in turn, affects their health. This study aimed to determine the associations between perceived built environment and leisure-time physical activity in Hangzhou, China. Methods 1440 participants aged 25-59 were randomly selected from 30 neighborhoods in three types of administrative planning units in Hangzhou. International Physical Activity Questionnaire long form and NEWS-A were used to obtain individual-level data. The China Urban Built Environment Scan Tool was used to objectively assess the neighborhood-level built environment. Multi-level regression was used to explore the relationship between perceived built environment variables and leisure-time physical activities. Data was collected in Hangzhou from June to December in 2012, and was analyzed in May 2013. Results Significant difference between neighborhood random variations in physical activity was identified (P=0.0134); neighborhood-level differences accounted for 3.0% of the variability in leisure-time physical activity. Male residents who perceived higher scores on access to physical activity destinations reported more involvement in leisure-time physical activity. Higher scores on perception of esthetic quality, and lower on residential density were associated with more time in leisure-time walking in women. Conclusions The present study demonstrated that perceived urban built environment attributes significantly correlate with leisure-time physical activity in Hangzhou, China. [ABSTRACT FROM AUTHOR]

Abstract: Cyclins are a family of diverse proteins that play fundamental roles in regulating cell cycle progression in Eukaryotes. Cyclins have been identified from protists to higher Eukaryotes, while its evolution remains vague and the findings turn out controversial. Current classification of cyclins is mainly based on their functions, which may not be appropriate for the systematic evolutionary analysis. In this work, we performed comparative and phylogenetic analysis of cyclins to investigate their classification, origin and evolution. Cyclins originated in early Eukaryotes and evolved from protists to plants, fungi and animals. Based on the phylogenetic tree, cyclins can be divided into three major groups designated as the group I, II and III with different functions and features. Group I plays key roles in cell cycle, group II varied in actions are kingdom (plant, fungi and animal) specific, and group III functions in transcription regulation. Our results showed that the dominating cyclins (group I) diverged from protists to plants, fungi and animals, while divergence of the other cyclins (groups II and III) has occurred in protists. We also discussed the evolutionary relationships between cyclins and cyclin-dependent kinases (CDKs) and found that the cyclins have undergone divergence in protists before the divergence of animal CDKs. This reclassification and evolutionary analysis of cyclins might facilitate understanding eukaryotic cell cycle control. [Copyright &y& Elsevier]

Abstract: Big defensins, endogenous cysteine-rich antimicrobial peptides (AMPs) with antimicrobial activity and immunomodulatory property, play crucial roles in host defense against various microbial pathogens. A novel big defensin (Sb-BDef1) of ark shell Scapharca broughtonii was identified by expressed sequence tag (EST) and RACE techniques. The Sb-BDef1 cDNA contained an open reading frame (ORF) of 336-bp encoding a polypeptide of 111 amino acids with a putative signal peptide of 21 amino acid residues, followed by a putative propeptide of 11 residues and a putative mature peptide of 79 residues. The mature peptide shared the common features of big defensins, including a high hydrophobic residues region (59%) in the N-terminus, a defensin domain in the C-terminus, which perfectly corresponds to the six conserved disulfide-bonded cysteine residues involved in the formation of the internal disulfide bridges (C1–C5, C2–C4 and C3–C6) in all big defensins from mollusk, horseshoe crab and amphioxus. Quantitative real-time PCR analysis revealed that the expression of Sb-BDef1 transcript was detected in all the tissues examined from normal ark shells, and the temporal expression of Sb-BDef1 mRNA was remarkably up-regulated at 8, 16 h in hemocytes, and at 16, 24 h in hepatopancreas after Vibrio anguillarum-challenge, respectively. These results suggested that Sb-BDef1 was a constitutive and inducible acute-phase protein and should be involved in immune response of Gram-negative microbial infection in ark shell S. broughtonii. [Copyright &y& Elsevier]

Abstract: Phenolic acid concentrations were determined in 37 Chinese commercial winter wheat cultivars grown at a single site over two seasons, and fractions comprising free and bound types were analyzed using HPLC with measurements of individual phenolic acids in each fraction. Most of the parameters were significantly influenced by cultivar, season, and their interaction effects, with cultivar variance being predominant. Wide ranges of concentration among the 37 cultivars were observed. The average concentration of bound type was 661 μg g−1 of dm, making up 97.5% of the phenolic acid determined with ferulic accounting for 70.7% of it, while free type made up only 2.5% of the phenolic acid determined with syringic accounting for 44.7% of it. Bound type was the predominant source to the grain phenolic acid concentrations determined. There were highly significant and positive correlations between bound ferulic concentration and total bound phenolic acid concentration, and between free syringic concentration and total free phenolic acid concentration. Cultivars Liangxing 66 and Zhongmai 895 were stable in concentration of components of phenolic acids across seasons, with high values of free and bound phenolic acids indicating they could be selected as parents in wheat breeding for health beneficial phenolic acid. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) are regulators of numerous cellular events; accumulating evidence indicates that miRNAs play a key role in a wide range of biological functions, such as cellular proliferation, differentiation, and apoptosis in cancer. Down-regulated expression of miR-145 has been reported in colon cancer tissues and cell lines. The molecular mechanisms underlying miR-145 and the regulation of colon carcinogenesis remain unclear. In this study, we investigated the levels of miR-145 in human colon cancer cells using qRT-PCR and found markedly decreased levels compared to normal epithelial cells. We identified PAK4 as a novel target of miR-145 using informatics screening. Additionally, we demonstrated that miR-145 targets a putative binding site in the 3′UTR of PAK4 and that its abundance is inversely associated with miR-145 expression in colon cancer cells; we confirmed this relationship using the luciferase reporter assay. Furthermore, restoration of miR-145 by mimics in SW620 cells significantly attenuated cell growth in vitro, in accordance with the inhibitory effects induced by siRNA mediated knockdown of PAK4. Taken together, these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth. [Copyright &y& Elsevier]

Abstract: β-Glucans have been shown to enhance immune responses for centuries, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Dectin-1, the C-type lectin receptor for β-glucan, is expressed abundantly on dendritic cells (DCs). Activation of DCs via Dectin-1 can lead to the maturation of DC, inducing both innate and adaptive immune responses against tumor development and microbial infection. In this study, we found that particulate yeast-derived β-glucans could induce the maturation of murine dendritic cell line D2SC/1 cells and increase the expression of mGITRL on D2SC/1 cells via Dectin-1/Syk pathway in a dose dependent manner. Furthermore, we demonstrated that the increased mGITRL on D2SC/1 cells could impair the suppressive activity of CD4+CD25+ regulatory T cells (Tregs) and enhance the proliferation of CD4+CD25− effector T cells (Teffs). These findings suggest that particulate β-glucan can be used as immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate immune suppressive activity, leading to a more efficient defense mechanism against tumor development or infectious diseases. [Copyright &y& Elsevier]

Abstract: Members of the Spred gene family are negative regulators of the Ras/Raf-1/ERK pathway, which has been associated with several features of the tumor malignancy. However, the effect of Spred genes on hepatocellular carcinoma (HCC) remains uninvestigated. In the present work, we analyzed the in vitro and in vivo effects of Spred2 expression on the hepatic carcinoma cell line, SMMC-7721. In addition to attenuated ERK activation, which inhibited the proliferation and migration of unstimulated and HGF-stimulated SMMC-7721 cells. Adenovirus-mediated Spred2 overexpression induced the activation of caspase-3 and apoptosis, as well as reduced the expression level of Mcl-1. Most importantly, the knockdown of Spred2 markedly enhanced tumor growth in vivo. In conclusion, these results suggest that Spred2 could qualify as a potential therapeutic target in HCC. [Copyright &y& Elsevier]

Background: The regulation of neuroendocrine hormones on the innate immune responses remains controversial. This report investigated the effects of exogenous norepinephrine with respect to macrophage function as well as to elucidate the underlying mechanism. Materials and Methods: The adherence, chemotaxis, phagocytosis, and cytokine production of macrophages were observed in the presence of increasing concentrations of norepinephrine. The expression of macrophage glucose response protein 78 (GRP78), X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6), and C-EBP homologous protein (CHOP) in macrophages was determined. The lentiviral vector pGCL-GFP-siXBP1 was cloned by inserting the annealed oligonucleotides encoding shRNAs specific for XBP1. Results: Norepinephrine exerted immunostimulatory effects on macrophage at low concentrations, while partial effects were observed at high concentrations. Low-dose norepinephrine induced an endoplasmic reticulum stress response, which was correlated with the immunostimulatory activities of norepinephrine. Levels of mRNA expression of XPB1, but not ATF6 or CHOP, was significantly increased only by low concentrations of norepinephrine. Inhibition of XBP1 expression with siRNA treatment significantly inhibited the immunostimulatory effects of low concentrations of norepinephrine. Conclusions: Our data convincingly indicated that norepinephrine exerted immunostimulatory actions on macrophages at low concentrations, suggesting that the underlying mechanisms are related to endoplasmic reticulum stress via XBP1. [ABSTRACT FROM AUTHOR]

Abstract: Apolipoprotein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the progression of glomerulosclerosis (GS). We conducted this investigation to explore whether all-trans retinoic acid (ATRA) could regulate the apoE expression in the pathological process of GS. 120 Wistar rats were divided into three groups at random: sham operation group (SHO), glomerulosclerosis model group without treatment (GS), GS model group treated with ATRA (GA); n=40, respectively. The disease of GS in rat was established by uninephrectomy and adriamycin (5mg/kg) injection. At the end of 9 and 13weeks, 20 rats in each group were killed and the relevant samples were collected. 24-hour urine total protein (24UTP), 24-hour urine excretion for albumin (24Ualb), serum total protein (TP) and serum albumin (Alb), blood urea nitrogen (BUN), serum creatinine (Scr), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), serum and urine apoE and glomerulosclerosis index (GSI) were measured. The protein expressions of collagen IV (Col-IV), fibronectin (FN) and apoE in glomeruli were determined by immunohistochemistry. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to detect the expression of apoE mRNA in kidney. TP and Alb in GA group in 9/13-week were increased than those of GS group, however, the differences were not statistically significant. Compared with group GS at 9/13weeks, values of 24UTP, 24Ualb, BUN, Scr, TC, TG, HDL, LDL, serum and urine apoE, and GSI in GA group that were significantly reduced, and protein expressions of Col-IV, FN and apoE in glomeruli and expression of apoE mRNA in renal tissue were significantly down-regulated by ATRA (P <0.01). In conclusion, ATRA can regulate the expression of apoE, reduce the accumulation of extracellular matrix (ECM) and step down the progression of GS. [Copyright &y& Elsevier]

Abstract: Spreds, a recently established class of negative regulators of the Ras–ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras–ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras–ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras–ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML. [Copyright &y& Elsevier]

Abstract: Endocrine glands-derived vascular endothelial growth factor (EG-VEGF, also termed as Prok1)—a novel cytokine that selectively acts on the endothelial cells of endocrine glands—was recently reported to be involved in the regulation of tumor cell growth and survival. However, its roles in the regulation of pancreatic cancer progression remain unclear. In this report, we investigated the suppressive effects of EG-VEGF on pancreatic cancer cell apoptosis and the relevant mechanisms. By using reverse-transcriptase polymerase chain reaction (RT-PCR) we found that the Mia PaCa II cells of the pancreatic cancer cell line express the mRNAs of both EG-VEGF (Prok1) and its receptors. EG-VEGF protects pancreatic cancer cells from apoptosis through upregulation of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic protein of the bcl-2 family. Treatment of pancreatic cancer cells with EG-VEGF results in the rapid phosphorylation of mitogen-activated protein kinase (MAPK), STAT3, and AKT, which are involved in the upregulation of Mcl-1 expression. EG-VEGF (Prok1) protects Mia PaCa II cells from apoptosis through G protein-coupled receptor (GPR)-induced activation of multiple signal pathways, and hence can be a novel target for pancreatic cancer therapy. [Copyright &y& Elsevier]

Abstract: β-glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAb therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (cetuximab) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients. [Copyright &y& Elsevier]

The design of a simple and efficient fluorescent probe for detecting hypochlorite (ClO−) is of great importance. Herein, we synthesized the hydroxyl-functionalized UiO-66 (UiO-66-(OH) 2) by the solvothermal method and its derivative aluminium ion-modified UiO-66-(OH) 2 (Al3+@UiO-66-(OH) 2) as two fluorescence probes are used for detecting ClO− in the water. The results showed that UiO-66-(OH) 2 has excellent fluorescent response ability for ClO− in water. Aluminium ion-modified UiO-66 (Al3+@UiO-66-(OH) 2) displayed its high efficiency for the fluorescence detection of ClO− with a response time of 30 ​s and extraordinary limit of detection of 1.63 ​μM in water. Moreover, the sensing of ClO− using easily portable Al3+@UiO-66-(OH) 2 -coated paper strips is also developed. Furthermore, the plausible fluorescence sensing mechanism of UiO-66-(OH) 2 for ClO− in aqueous solution was also discussed. Hydroxyl-functionalized and Al3+-modified UiO-66 for detecting ClO− are proposed.UiO-66-(OH) 2 and Al3+@ UiO-66-(OH) 2 shows superior fluorescence intensity. Moreover, Al3+@ UiO-66-(OH) 2 sensor shows highly sensitive and selective to detect ClO-. Portable Al3+@UiO-66-(OH)2-coated paper strips are developed for detecting ClO. [Display omitted] • Hydroxyl-functionalized and Al3+-modified UiO-66 for detecting ClO− are proposed. • UiO-66-(OH) 2 and Al3+@ UiO-66-(OH) 2 shows superior fluorescence intensity. • Al3+@ UiO-66-(OH) 2 sensor shows highly sensitive and selective to detect ClO-. • Portable Al3+@UiO-66-(OH) 2 -coated paper strips are developed for detecting ClO−. [ABSTRACT FROM AUTHOR]

Abstract: The therapeutic benefits of fungal β-glucans have been demonstrated as immuno-stimulating agents. In this study, we aimed to explore the mechanisms used by yeast β-glucan-rich particles to activate murine resident macrophages for cytokine secretion. We demonstrated that resident macrophages were effectively activated by whole yeast β-glucan particles (WGPs), such as with the upregulation of co-stimulatory molecules and the secretion of cytokines. The binding ability of WGPs and the levels of cytokine secretion in resident macrophages were significantly inhibited by soluble yeast β-glucan but not by blockade of zymosan glucan receptor dectin-1. In addition, WGP-stimulated cytokine secretion was partially dependent on the MyD-88 pathway but was not significantly affected in CR3-deficient (CR3−/−) mice. Furthermore, we showed that Syk kinase was recruited upon WGP stimulation and was required for the production of cytokines. Taken together, these observations suggest that β-glucan recognition is necessary but not sufficient to induce inflammatory response on resident macrophages. In addition, β-glucan particles may use differential mechanisms for cytokine secretion in resident macrophages that may modulate both innate and adaptive immunity. [Copyright &y& Elsevier]