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Predicting the effects of rising temperature entails measuring both habitat thermal characteristics and the physiological variation of the species as it relates to this microhabitat variation; these two types of measurements can generate what is termed a 'physiological landscape' for the species. Mapping the micro‐scale physiological landscape across space and time, rather than relying on large‐scale averages of temperature and means of thermal limits in a species, can allow more accurate estimates of an organism's sensitivity to temperature change and support development of more refined models of the impacts of anthropogenic climate change that have higher predictive power.We thus continually monitored the body (operative) temperature of the intertidal mussel Mytilisepta virgata in both sun‐exposed and shaded microhabitats and determined the seasonal variations of cardiac performance of field‐acclimatized and laboratory‐acclimated mussels from different microhabitats for calculating the thermal sensitivity, as indicated by the difference between the maximum ambient temperature and an individual's upper thermal limit (thermal safety margin, TSM), in each microhabitat and each month.The mussels experienced divergent thermal stress, in average temperature, acute and chronic thermal stress and thermal predictivity among different microhabitats, and presented high spatial–temporal variations of cardiac function as results of seasonal acclimatization and inter‐individual variations. Results of TSMs indicated that the thermal sensitivities of the mussels to high temperature were season‐ and microhabitat specific, and the mussels in the shaded microhabitats were predicted to survive the hottest summer temperatures; however, some individuals in the sun‐exposed microhabitats experienced temperatures above their sublethal temperature.With the large, high‐resolution dataset of thermal environmental characteristics and the cardiac performances with high variations, we were able to integrate the effects of synchronized changes in microenvironmental temperatures and cardiac thermal responses and thereby characterize the physiological landscape of thermal sensitivity. The complex physiological landscape that exists in the intertidal zone must be taken into account when predicting the effects of changes in environmental temperature, such as those occurring with global climate change. A free Plain Language Summary can be found within the Supporting Information of this article. [ABSTRACT FROM AUTHOR]

Drugs produce their therapeutic effects by modulating specific targets, and there are 89 innovative targets of first-in-class drugs approved in 2004–17, each with information about drug clinical trial dated back to 1984. Analysis of the clinical trial timelines of these targets may reveal the trial-speed differentiating features for facilitating target assessment. Here we present a comprehensive analysis of all these 89 targets, following the earlier studies for prospective prediction of clinical success of the targets of clinical trial drugs. Our analysis confirmed the literature-reported common druggability characteristics for clinical success of these innovative targets, exposed trial-speed differentiating features associated to the on-target and off-target collateral effects in humans and further revealed a simple rule for identifying the speedy human targets through clinical trials (from the earliest phase I to the 1st drug approval within 8 years). This simple rule correctly identified 75.0% of the 28 speedy human targets and only unexpectedly misclassified 13.2% of 53 non-speedy human targets. Certain extraordinary circumstances were also discovered to likely contribute to the misclassification of some human targets by this simple rule. Investigation and knowledge of trial-speed differentiating features enable prioritized drug discovery and development. [ABSTRACT FROM AUTHOR]

The function of a protein is of great interest in the cutting-edge research of biological mechanisms, disease development and drug/target discovery. Besides experimental explorations, a variety of computational methods have been designed to predict protein function. Among these in silico methods, the prediction of BLAST is based on protein sequence similarity, while that of machine learning is also based on the sequence, but without the consideration of their similarity. This unique characteristic of machine learning makes it a good complement to BLAST and many other approaches in predicting the function of remotely relevant proteins and the homologous proteins of distinct function. However, the identification accuracies of these in silico methods and their false discovery rate have not yet been assessed so far, which greatly limits the usage of these algorithms. Herein, a comprehensive comparison of the performances among four popular prediction algorithms (BLAST, SVM, PNN and KNN) was conducted. In particular, the performance of these methods was systematically assessed by four standard statistical indexes based on the independent test datasets of 93 functional protein families defined by UniProtKB keywords. Moreover, the false discovery rates of these algorithms were evaluated by scanning the genomes of four representative model organisms (Homo sapiens, Arabidopsis thaliana, Saccharomyces cerevisiae and Mycobacterium tuberculosis). As a result, the substantially higher sensitivity of SVM and BLAST was observed compared with that of PNN and KNN. However, the machine learning algorithms (PNN, KNN and SVM) were found capable of substantially reducing the false discovery rate (SVM < PNN < KNN). In sum, this study comprehensively assessed the performance of four popular algorithms applied to protein function prediction, which could facilitate the selection of the most appropriate method in the related biomedical research. [ABSTRACT FROM AUTHOR]

The selection of the right drug targets is critically important for the successful and cost-effective development and clinical testing of drugs. A 2009 paper reported an in silico prospective prediction of the clinical potential of 156 targets of clinical trial drugs (all of these targets were without an approved drug at the time of the paper’s publication). Eight years later, the assessment of the clinical status of these targets revealed impressive capability of the in silico method in prospectively predicting the clinical success of drug targets. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear. Methods: Twelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis. Results: EBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells. Conclusion: In this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details. Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML. [ABSTRACT FROM AUTHOR]

The proliferation of coastal infrastructure in the context of coastal development, urbanization, and global change is inevitably related to the transformation of coastal community structure. For restoration of biodiversity in these human-disturbed coastal ecosystems, it is vital to untangle the community structure and thermal environments, with the consideration of the microhabitat-scale thermal environment variations. In the present study, we measured the species richness, α-diversity (i.e. the species composition of each surface of breakwaters), and β-diversity (i.e. the dissimilarities among macrobenthic communities of different surfaces of breakwater) of macrobenthos on the breakwaters on a tropical shore for understanding the variation of the community structure of macrobenthos; we also monitored the operative temperatures in different surfaces of the breakwaters during the experimental period for investigating the roles of microhabitat thermal environment on the community structure of macrobenthos on the artificial infrastructure. Our results showed that there were higher species richness and abundance in the thermally benign microhabitats. The variations of β-diversity indicated that the community structure underwent dramatic changes in different microhabitats and seasons. The population dynamics of thermal-sensitive species (e.g. Patelloida pygmaea , Cellana toreuma , and Siphonaria japonica) largely contributed to the changes in community structure. Redundancy analysis (RDA) results showed that maximum temperature, temperature predictability (i.e. the degree to which a temperature data point in a time series is influenced by its historical values), and heating rate were important thermal characteristics driving community structure on the artificial infrastructure. These results indicate the heterogeneity of thermal environments among different microhabitats is crucial for maintaining the community structure of macrobenthos on the artificial infrastructure and suggest that structural complexity should be considered for biodiversity conservation in the design and construction of coastal infrastructure. [Display omitted] • The distribution of macrobenthos on the artificial shoreline showed strong variation among different microhabitats. • Changes of distribution of the thermal-sensitive species contributed mostly to the changes of community structure. • High temperature, temperature predictivity and heating rate drive species distribution among microhabitats. • Microhabitat complexity should be considered for biodiversity conservation in the construction of coastal infrastructures. [ABSTRACT FROM AUTHOR]

Background Pediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear. Methods Twelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis. Results EBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells. Conclusion In this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details. [ABSTRACT FROM AUTHOR]

Background Histone acetyltransferase (HAT) inhibitors can inhibit proliferation and induce apoptosis in cancer cell lines. The novel cell-permeable p300/CREB-binding protein (CBP)-selective HAT inhibitor HATi II can reduce histone H3 acetylation and induce chromatin condensation in HeLa cells. Here, we examined the effects and mechanism of action of HATi II in glioma cell lines. Methods Cell viability was assessed using the CCK-8 assay. Cell cycle analysis was performed using flow cytometry. Apoptosis was evaluated using Annexin V staining and flow cytometry, Hoechst 33342 staining and the TUNEL assay. Expression and cleavage of caspase-3, caspase-9 and poly ADP-ribose polymerase (PARP) were assessed by Western blotting. Statistical analysis was performed using two-tailed Student's t-tests. The gene expression profiles of U251 glioma cells treated with HATi II or DMSO were analyzed using the Arraystar Human 8 x 60 K LncRNA/mRNA expression array; data was analyzed using MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profiles (≥2-fold) derived from the cluster analyses were subjected to gene ontology and pathway analysis. Results HATi II inhibited the proliferation of U251, U87, HS683 and SHG44 cells in a dosedependent manner. HATi II induced cell cycle arrest at the G2/M phase, and induced significant levels of apoptosis, apoptotic body formation and DNA fragmentation in HATi IItreated U251 and SHG44 cells. HATi II induced cleavage of caspase-3, caspase-9 and PARP in U251 and SHG44 cells. In HATi II-treated U251 cells, 965 genes were upregulated, 984 genes were downregulated and 3492/33327 lncRNAs were differentially expressed. GO analysis showed the differentially expressed genes with known functions are involved in a variety of processes; alcoholism, p53 signaling pathway, cytokine-cytokine receptor interaction and transcriptional mis-regulation in cancer were the four most significant pathways. Upregulation of p53 signaling pathway-related genes in HATi II-treated cells was confirmed by quantitative RT-PCR and Western blotting. Conclusions HATi II inhibits proliferation and induces apoptosis via the caspase-dependent pathway in human glioma cell lines, possibly by activating the p53 signaling pathway. HATi II deserves further investigation as a novel treatment for glioma. [ABSTRACT FROM AUTHOR]

Background Acute myeloid leukemia (AML) is the second most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature in various tumors, including AML. Metallothionein III (MT3) is a tumor suppresser reported to show promoter hypermethylated in various cancers. However, the expression and molecular function of MT3 in pediatric AML is unclear. Methods Eleven human leukemia cell lines and 41 pediatric AML samples and 20 NBM/ITP (Norma bone marrow / Idiopathic thrombocytopenic purpura) control samples were analyzed. Transcription levels of MT3 were evaluated by semi-quantitative and real-time PCR. MT3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BSG). The molecular mechanism of MT3 was investigated by apoptosis assays and PCR array analysis. Results The MT3 promoter was hypermethylated in leukemia cell lines. More CpG's methylated of MT3 was observed 39.0% pediatric AML samples compared to 10.0% NBM controls. Transcription of MT3 was also significantly decreased in AML samples compared to NBM/ITP controls (P < 0.001); patients with methylated MT3 exhibited lower levels of MT3 expression compared to those with unmethylated MT3 (P = 0.049). After transfection with MT3 lentivirus, proliferation was significantly inhibited in AML cells in a dose-dependent manner (P < 0.05). Annexin V assay showed that apoptosis was significantly upregulated MT3-overexpressing AML cells compared to controls. Real-time PCR array analysis revealed 34 dysregulated genes that may be implicated in MT3 overexpression and apoptosis in AML, including FOXO1. Conclusion MT3 may be a putative tumor suppressor gene in pediatric AML. Epigenetic inactivation of MT3 via promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Overexpression of MT3 may inhibit proliferation and induce apoptosis in AML cells. FOXO1 was dysregulated in MT3-overexpressing cells, offering an insight into the mechanism of MT3-induced apoptosis. However, further research is required to determine the underlying molecular details. [ABSTRACT FROM AUTHOR]

Erythrocytosis moderately enhances the oxygen-carrying capacity of the blood and is considered a characteristic response of individuals adapting from low-altitude regions to high-altitude regions. Nevertheless, erythrocytosis can also turn excessive and result in maladaptive syndromes, such as high altitude polycythemia (HAPC). The increased differentiation or proliferation of erythroid cells in the bone marrow may be a crucial factor leading to accumulation of peripheral erythroid cells. However, the mechanism of erythroid regulation within the bone marrow of high-altitude erythrocytosis remains insufficiently systematically observed. We utilized single-cell transcription sequencing to characterize bone marrow cells following chronic hypoxic exposure and found that bone marrow erythrocytosis is associated with the accumulation of Baso-E, Poly-E, and Ortho-E cells at the terminal stage of erythroid lineage differentiation. Through analysis of differential gene expression and localization in differentiated cells within the erythroid lineage, we confirmed that DDIT4 expression was localized in advanced differentiated erythroblast including Baso-E, Poly-E and Ortho-E, its expression was significantly enhanced by hypoxia exposure. We demonstrated that overexpression of DDIT4 could promote K562 cell differentiation, and through the IP pull-down interaction protein profile, we found that DDIT4 might participate in regulating the cell cycle by interacting with SIPA1 to promote the proliferation of erythroid cells and may be involved in HAPC. • The bone marrow single-cell RNA atlas of Rat in high altitude erythrocytosis were comprehensively illuminated. • Baso-E, Poly-E, and Ortho-E accumulation and the overexpression of DDIT4 in them are the main causes of high altitude erythrocytosis. • DDIT4 promotes erythropoiesis by regulating the cell cycle in coordination with SIPA1. [ABSTRACT FROM AUTHOR]

The roles of synonymous mutations for adapting to stressful thermal environments are of fundamental biological and ecological interests but poorly understood. To study whether synonymous mutations influence thermal adaptation at specific microhabitats, a genome-wide genotype-phenotype association analysis is carried out in the black mussels Mytilisepta virgata. A synonymous mutation of Ubiquitin-specific Peptidase 15 (MvUSP15) is significantly associated with the physiological upper thermal limit. The individuals carrying GG genotype (the G-type) at the mutant locus possess significantly lower heat tolerance compared to the individuals carrying GA and AA genotypes (the A-type). When heated to sublethal temperature, the G-type exhibit higher inter-individual variations in MvUSP15 expression, especially for the mussels on the sun-exposed microhabitats. Taken together, a synonymous mutation in MvUSP15 can affect the gene expression profile and interact with microhabitat heterogeneity to influence thermal resistance. This integrative study sheds light on the ecological importance of adaptive synonymous mutations as an underappreciated genetic buffer against heat stress and emphasizes the importance of integrative studies at a microhabitat scale for evaluating and predicting the impacts of climate change. Synonymous mutations are shown to affect the gene expression profile and interact with microhabitat heterogeneity to influence thermal resistance in black mussels. [ABSTRACT FROM AUTHOR]

[Display omitted] • The relationship between active ingredients deposition and control efficacy was established. • The synergism of adjuvants by promoting the penetration process of fludioxonil active ingredients through target leaves. • The secondary distribution of active ingredients on the target leaves was observed. In this study, pot and field experiments showed that S903, Hasten and Gemini-31511 can significantly enhanced the control efficacy of fludioxonil on cucumber anthracnose. Then by studying the deposition and penetration interaction between active ingredients and cucumber leaves to revealed how the adjuvants influence the interaction process between pesticide active ingredients and target plants to improve the control efficacy. By analysis the effect of fludioxonil deposition to synergism of adjuvants, indicated that fludioxonil active ingredient deposition caused by adjuvants was not the main factor for the adjuvants synergistic effect. Fludioxonil + S903 yielded the lowest surface tension and contact angle, which also implying the best wetting ability. The mean diameters in Hasten + fludioxonil group were much smaller than those in only fludioxonil group (5.39 μm–90 g a.i. ha−1, 5.50 μm–180 g a.i. ha−1), the average particle size only had 3.45 μm (90 g a.i. ha−1) and 3.94 μm (180 g a.i. ha−1). And the result of spray droplets was consistent with the particles of fludioxonil crystals observed on glass slides and cucumber leaves. Therefore, S903 improved the penetrability of fludioxonil in the target plants by improving the wetting and dispersion of active ingredients on the target interface. Meantime, Hasten improved the penetrability of fludioxonil in the target plants by decreasing the particle size of active ingredients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease associated with long non-coding RNAs and DNA methylation; however, the mechanisms underlying the role of lncRNA small nucleolar RNA host gene 1 (lncRNA SNHG1) and subsequent involvement of DNA methylation in AD development are not known. The aim of this study was to examine the regulatory mechanisms attributed to lncRNA SNHG1 gene utilizing 2 strains of senescence-accelerated mouse prone 8 (SAMP8) model of AD and compared to senescence-accelerated mouse resistant (SAMR) considered a control. Both strains of the mouse were transfected with either blank virus, psLenti-U6-SNHG1(low gene expression) virus, and psLenti-pA-SNHG1(gene overexpression) virus via a single injection into the brains for 2 weeks. At 2 weeks mice were subjected to a Morris water maze to determine any behavioral effects followed by sacrifice to extract hippocampal tissue for Western blotting to measure protein expression of p-tau, DNMT1, DNMT3A, DNMT3B, TET1, and p-Akt. No marked alterations were noted in any parameters following blank virus transfection. In SAMP8 mice, a significant decrease was noted in protein expression of DNMT1, DNMT3A, DNMT3B, and p-Akt associated with rise in p-tau and TET1. Transfection with ps-Lenti-U6-SNHG1 alone in SAMR1 mice resulted in a significant rise in DNMTs and p-Akt and a fall in p-tau and TET1. Transfection of SAMP8 with ps-Lenti-U6-SNHG1 blocked effects on overexpression noted in this mouse strain. However, knockdown of lncRNA SNHG1 yielded the opposite results as found in SAMR1 mice. In conclusion, the knockdown of lncRNA SNHG1 enhanced DNA methylation through the PI3K/Akt signaling pathway, thereby reducing the phosphorylation levels of tau in SAMP8 AD model mice with ameliorating brain damage attributed to p-tau accumulation with consequent neuroprotection. [ABSTRACT FROM AUTHOR]

Vascular dementia (VD) a heterogenous group of brain disorders in which cognitive impairment is attributable to vascular risk factors and cerebrovascular disease. A common phenomenon in VD is a dysfunctional cerebral regulatory mechanism associated with insufficient cerebral blood flow, ischemia and hypoxia. Under hypoxic conditions oxygen supply to the brain results in neuronal death leading to neurodegenerative diseases including Alzheimer's (AD) and VD. In conditions of hypoxia and low oxygen perfusion, expression of hypoxia-inducible factor 1 alpha (HIF-1α) increases under conditions of low oxygen and low perfusion associated with upregulation of expression of hypoxia-upregulated mitochondrial movement regulator (HUMMR), which promotes anterograde mitochondrial transport by binding with trafficking protein kinesin 2 (TRAK2). Schisandrin B (Sch B) an active component derived from Chinese herb Wuweizi prevented β-amyloid protein induced morphological alterations and cell death using a SH-SY5Y neuronal cells considered an AD model. It was thus of interest to determine whether Sch B might also alleviate VD using a rat bilateral common carotid artery occlusion (BCAO) dementia model. The aim of this study was to examine the effects of Sch B in BCAO on cognitive functions such as Morris water maze test and underlying mechanisms involving expression of HIF-1α, TRAK2, and HUMMR levels. The results showed that Sch B improved learning and memory function of rats with VD and exerted a protective effect on the hippocampus by inhibition of protein expression of HIF-1α, TRAK2, and HUMMR factors. Evidence indicates that Sch B may be considered as an alternative in VD treatment. [ABSTRACT FROM AUTHOR]

Temperature plays a major role in controlling species' distributions, and small-scale variation in the thermal environment are potentially an important factor that governs distributions on a local scale. For untangling the roles of behavioral and physiological adaptations on species' distribution at a small-scale level, we carried out a comparative study of two mudflat snails (genus Cerithidea) by determining these congeners' burying behavior, lethal temperature, cardiac performance and heat-shock protein (hsp70) gene expression. These two sympatric snails occupy different microhabitats on the upper intertidal mudflat. During periods of emersion, C. cingulata inhabits the open mudflat and C. largillierti usually aggregates around small rocks on the upper intertidal mudflat. Our results indicate that the two Cerithidea congeners show different behavioral and physiological responses to high temperature. Compared to C. largillierti , C. cingulata prefers to bury into the mud, has a higher thermal limit and a higher level of inducible expression of hsp7 0 mRNA, implying important roles of behavioral and physiological adaptations to the harsh thermal environment on the open mudflat. Furthermore, results of generalized additive modelling (GAM) analysis of cardiac performance and coefficient of variation (CV) of hsp7 0 mRNA expression showed high inter-individual variation in C. cingulata. These results highlight the importance of behavioral and physiological adaptions in sympatric species' distributions on the mudflat and help to shed light on the mechanisms of how small-scale differences in the thermal environment shape sympatric species' distributions. • Two Cerithidea snails with divergent habitat-use strategies occupy different microhabitats on the upper intertidal mudflat. • Behavioral and physiological responses to high temperature were examined. • The two Cerithidea congeners show different behavioral and physiological responses to high temperature. • Compared to C. largillierti , C. cingulata prefers to bury into the mud, has a higher thermal limit and a higher level of inducible expression of hsp7 0 mRNA. • Our results highlight the importance of behavioral and physiological adaptions in distributions of the mudflat snails. [ABSTRACT FROM AUTHOR]

Rationale: Improving the analytical performance of linear ion traps (LITs) is crucial for the advancement of high‐performance LIT mass spectrometers. In this study, a double resonant excitation method was employed in an asymmetric LIT to achieve high ion unidirectional ejection efficiency and enhanced mass resolution. Methods: The asymmetric trapping field was generated by stretching one x electrode with a distance α. The double resonant excitation was achieved by applying an alternating voltage out of phase and a supplementary alternating voltage in phase to the x and y electrode pairs of the LIT, respectively. Numerical simulations of ion trajectories were performed to validate the effectiveness of this method. Results: The mass resolution of the asymmetric LIT with double resonant excitation could be improved to ~3800, which was over two times compared to that with only dipolar resonant excitation, while both reached ~90% in ion unidirectional ejection efficiency. Conclusions: By employing the double resonant excitation method, the mass resolution could be improved significantly in the asymmetric LIT, while maintaining a considerably high ion unidirectional ejection efficiency. This method might provide a general solution for enhancing ion detection efficiency and mass resolution of LIT mass spectrometers. [ABSTRACT FROM AUTHOR]

The different life-history stages of organisms may have divergent thermal limits and thus respond differently to global warming. For comprehensive understanding of the ecological impacts of global warming, it is crucial to determine thermal limits among different life stages and to understand how close an organism lives to its thermal limits at different life stages. Here, we measured the effect of temperature on hatching and the lethal temperature (LT, lethal temperature of 50%) of larvae to explore effects of high temperature on the encapsulated and planktonic stages of the pulmonate limpet Siphonaria japonica. We measured cardiac performance to determine adult limpets' thermal limit. At the encapsulated stage, heat shock at 34.5 °C affected larval hatching significantly. Pelagic larvae showed a high LT (45.03 °C), indicating a high thermal tolerance for the pelagic larval stage. For the adults, the Arrhenius break temperature and flatline temperature were 38.49 ± 1.27 and 44.27 ± 1.08 °C, respectively. The integrated study of environmental temperatures and thermal sensitivities at different life stages of S. japonica indicates that the egg ribbon and adult stages are potentially most sensitive to the future temperature increases on subtropical shores. [ABSTRACT FROM AUTHOR]

Background: Overexpression of cyclin D1 dependent kinases 4 and 6 (CDK4/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both CDK4 and 6. To date, the molecular function of LEE011 in leukemia remains unclear. Methods: Leukemia cell growth and apoptosis following LEE011 treatment was assessed through CCK-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by β-galactosidase staining and p16INK4a expression analysis. Gene expression profiles of LEE011 treated HL-60 cells were investigated using an Arraystar Human LncRNA array. Gene ontology and KEGG pathway analysis were then used to analyze the differentially expressed genes from the cluster analysis. Results: Our studies demonstrated that LEE011 inhibited proliferation of leukemia cells and could induce apoptosis. Hoechst 33,342 staining analysis showed DNA fragmentation and distortion of nuclear structures following LEE011 treatment. Cell cycle analysis showed LEE011 significantly induced cell cycle G1 arrest in seven of eight acute leukemia cells lines, the exception being THP-1 cells. β-Galactosidase staining analysis and p16INK4a expression analysis showed that LEE011 treatment can induce cell senescence of leukemia cells. LncRNA microarray analysis showed 2083 differentially expressed mRNAs and 3224 differentially expressed lncRNAs in LEE011-treated HL-60 cells compared with controls. Molecular function analysis showed that LEE011 induced senescence in leukemia cells partially through downregulation of the transcriptional expression of MYBL2. Conclusions: We demonstrate for the first time that LEE011 treatment results in inhibition of cell proliferation and induction of G1 arrest and cellular senescence in leukemia cells. LncRNA microarray analysis showed differentially expressed mRNAs and lncRNAs in LEE011-treated HL-60 cells and we demonstrated that LEE011 induces cellular senescence partially through downregulation of the expression of MYBL2. These results may open new lines of investigation regarding the molecular mechanism of LEE011 induced cellular senescence. [ABSTRACT FROM AUTHOR]

The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology. [ABSTRACT FROM AUTHOR]

Background: Wilms tumor (WT) is an embryonic kidney cancer, for which histone acetylation might be a therapeutic target. LBH589, a novel targeted agent, suppresses histone deacetylases in many tumors. This study investigated the antitumor activity of LBH589 in SK-NEP-1 and G401 cells. Methods: SK-NEP-1 and G401 cell growth was assessed by CCK-8 and in nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometry detected apoptosis in cell culture. Gene expressions of LBH589-treated tumor cells were analyzed using an Arraystar Human LncRNA Array. The Multi Experiment View cluster software analyzed the expression data. Differentially expressed genes from the cluster analyses were imported into the Ingenuity Pathway Analysis tool. Results: LBH589 inhibited cell proliferation of SK-NEP-1 and G401 cells in a dose-dependent manner. Annexin V, TUNEL and Hochest 33342 staining analysis showed that LBH589-treated cells showed more apoptotic features compared with the control. LBH589 treatment inhibited the growth of SK-NEP-1 xenograft tumors in nude mice. Arraystar Human LncRNA Array analysis of genes and lncRNAs regulated by LBH589 identified 6653 mRNAs and 8135 lncRNAs in LBH589-treated SK-NEP-1 cells. The most enriched gene ontology terms were those involved in nucleosome assembly. KEGG pathway analysis identified cell cycle proteins, including CCNA2, CCNB2, CCND1, CCND2, CDK4, CDKN1B and HDAC2, etc. Ingenuity Pathway Analysis identified important upstream molecules: HIST2H3C, HIST1H4A, HIST1A, HIST1C, HIST1D, histone H1, histone H3, RPRM, HSP70 and MYC. Conclusions: LBH589 treatment caused apoptosis and inhibition of cell proliferation of SK-NEP-1and G401 cells. LBH589 had a significant effect and few side effects on SK-NEP-1 xenograft tumors. Expression profiling, and GO, KEGG and IPA analyses identified new targets and a new “network” of genes responding to LBH589 treatment in SK-NEP-1 cells. RPRM, HSP70 and MYC may be important regulators during LBH589 treatment. Our results provide new clues to the proapoptotic mechanism of LBH589. [ABSTRACT FROM AUTHOR]

Aiming at the problem that the driving principle of asymmetric vibration was difficult to analyzed in the inertial piezoelectric precise actuators, the simple pendulum with asymmetric structure was proposed. Firstly its model structure and motion principle were discussed. After constructing the nonlinear dynamic equation, the working characteristics was analyzed in two major areas: energy transformation and period of motion. Then, the prototype was designed and fabricated. A series of experiments were performed to test the impact of the initial releasing angle θ0, center distance R and length L1 on the period of motion. The research results indicate that the pendulum length, maximum angle and half period on each side are all different. The motion period of asymmetric single pendulum under large angle condition increases with the increase of the initial releasing angle θ0 and length L1, but decreases with the increase of the center distance R. The theoretical results of the period are coincident very well with the experiments. The results of the working characteristics of the simple pendulum with asymmetric structure lay the foundation of the development and design of inertial piezoelectric precise actuators. [ABSTRACT FROM AUTHOR]

Aim: Rapid anthropogenic warming coupled with changes in land use is altering the distributions of species, with consequences for ecosystem functioning and services. It is crucial to evaluate species range shifts based on understanding of the interaction of temperature with non‐climatic factors such as habitat availability and dispersal potential. Here, we aim to investigate roles of environmental temperature, habitat availability and population connectivity on the distributions of hard‐shore intertidal animals. We further examine potential roles of extensive artificial seawall construction in enabling poleward expansion of species in China, thus reshaping coastal biogeography. Location: Chinese coast. Time period: 2013–2017. Major taxa studied: Intertidal invertebrates. Methods: We took an integrative approach encompassing distributional ecology, thermal physiology, molecular genetics, heat budget modelling and larval dispersal to elucidate how interacting multiple drivers, including temperature, habitat availability and larval dispersal, determine distributions of hard‐shore invertebrates, focusing on what sets their range edges at a boundary between biogeographic provinces. Results: Our results untangle the complex interactions of global climate change with the impacts of regional scale coastal development. Temperature, larval transport and habitat availability are the major proximate factors controlling the range limits of coastal marine species. The artificial shorelines provide suitable habitats for hard‐shore species on the Yangtze River Delta, and minimum temperature in winter is an important factor setting the new northern range limit of these hard‐shore species along the Chinese coast. Main conclusions: In the face of global warming and global sprawl of marine hard infrastructure, species distributions, community structures and biogeographic patterns are experiencing dramatic changes. The combined influence of multiple human stressors including climate change and artificial shorelines can be evaluated by using a multidisciplinary framework, including ecological distribution, physiological sensitivity of species to these stressors, and the role of dispersal in maintaining population connectivity. [ABSTRACT FROM AUTHOR]

Abstract In this study, the bioactivities of binary mixtures of organosilicone surfactants and indoxacarb against two Lepidopteran pests were investigated along with their environmental risks. All of the tested organosilicone surfactants had obvious synergistic effects on the contact toxicity of indoxacarb against Spodoptera exigua and Agrotis ipsilon. However, all of the organosilicone surfactants exhibited certain antagonism for indoxacarb against S. exigua in terms of stomach & contact toxicity; both Silwet-408 and Silwet-806 exhibited additivity against A. ipsilon , whereas Silwet-618 and Silwet-DRS-60 exhibited synergism and slight antagonism, respectively. All of the tested chemicals were highly toxic to Daphnia magna , among which Silwet-DRS-60 had the lowest acute toxicity (EC 50 of 94.91 μg/L). However, these chemicals were less toxic to Brachydanio rerio. Silwet-DRS-60 had a low toxicity to B. rerio , while Silwet-408, Silwet-806 and Silwet-618 were moderately toxic to B. rerio. For the joint toxicity evaluation of organosilicone surfactants and indoxacarb to D. magna and B. rerio , the additive index method, concentration addition method and toxicity unit method were robust in judging synergism or antagonism, whereas other methods were more conservative; the V-value method and equilibrium curve method exhibited high robustness and viability in evaluating the combined effects of binary mixtures. Overall, we should carefully select organosilicone surfactants for premixed or tank-mixed pesticides in agriculture to obtain a balance between synergistic effects on pests and environmental risks. Graphical abstract Image Highlights • Organosilicone were synergistic on the contact toxicity of indoxacarb. • Organosilicone were highly toxic to D. magna but less toxic to B. rerio. • Additive index, concentration addition and toxicity unit were robust. • V-value and equilibrium curve were conservative in the joint toxicity evaluation. [ABSTRACT FROM AUTHOR]

Abstract Seeking alternatives for alkylphenol ethoxylates (APEOs) have been a heavily researched topic in the surfactant industry and agricultural systems. In this study, the combined effects of different ethoxylates and pesticides on the bioactivity against three pests and toxicological risks to Daphnia magna were investigated. Results showed that alcohol ethoxylates (AEOs) had higher synergistic effects on the bioactivity of pesticides against Spodoptera exigua , Agrotis ipsilon and Aphis citricola than did APEOs. In terms of the joint toxicity of the ethoxylates and pesticides to D. magna , additive index method, toxicity unit method, V value method and isobologram method were used in the tests. All of these methods indicated that the joint effects of APEOs + acetamiprid and APEOs + indoxacarb upon D. magna turned from synergism to antagonism with the increasing EO (ethylene oxide) numbers. Those of AEOs exhibited similar trends. Overall, AEOs may be potential alternatives for APEOs in agriculture as they synergize pesticides against three pests significantly more than do APEOs. However, further research should investigate the compounds' environmental risks to aquatic organisms because the AEOs were highly toxic to D. magna. Graphical abstract Unlabelled Image Highlights • AEOs had higher synergistic effects on pesticides than APEOs. • Additive index, toxicity unit, V value and isobologram methods were integrated. • Synergistic ratios and toxicities of AEOs and APEOs decreased with the EO numbers. • AEOs may be potential alternatives for APEOs in agricultural production system. [ABSTRACT FROM AUTHOR]

The abnormal expression of nuclear paraspeckle assembly transcript 1 (NEAT1) may serve critical functions for the development and progression of various types of human tumor. However, the expression and biological function of NEAT1 in hepatoblastoma (HB) and the underlying mechanisms for the function of NEAT1 in HB remain largely uncharacterized. In the present study, the results of reverse transcription-quantitative polymerase chain reaction revealed that the expression of NEAT1 was significantly elevated in HB tissues. HB tissues with metastasis also exhibited significantly increased levels of NEAT1 compared with tissues without metastasis. The biological functions of NEAT1 were then assessed using gain-/loss-of-function studies. The results of in vitro assays revealed that inhibiting NEAT1 expression reduced the migration and invasion of HepG2 cells. By contrast, the induced expression of NEAT1 exhibited the opposite effect. The present study also demonstrated that the inhibition of NEAT1 expression prevented the epithelial-mesenchymal transition of HepG2 cells, whereas forced expression of NEAT1 exhibited the opposite effect. In addition, it was confirmed that NEAT1 could modulate the expression of microRNA (miR)-129-5p in HepG2 cells, and that NEAT1 may exert its effect on the metastatic behaviors and epithelial-mesenchymal transition of HepG2 cells by inhibiting miR-129-5p. In conclusion, the present study indicated that NEAT1 expression was aberrantly increased in HB and that it may promote the metastasis of HB cells by inhibiting miR-129-5p. Targeting NEAT1 may potentially be a novel therapeutic option for treating patients with HB. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) is a promising approach to control Leptinotarsa decemlineata . In this study, RNAi efficiency by double-stranded RNA (dsRNA) targeting S-adenosyl-L-homocysteine hydrolase ( LdSAHase ) was compared among L. decemlineata first- to fourth-instar larvae. Ingesting ds LdSAHase successfully decreased the target gene expression, caused lethality, inhibited growth and impaired pupation in an instar- and concentration-dependent manner. To study the role of Dicer2 and Argonaute2 genes in RNAi efficiency, we identified LdDcr2a , LdDcr2b , LdAgo2a and LdAgo2b . Their expression levels were higher in young larvae than those in old ones. Exposure to ds egfp for 6 h significantly elevated LdDcr2a , LdDcr2b , LdAgo2a and LdAgo2b mRNA levels in the first-, second-, third- and fourth-instar larvae. When the exposure periods were extended, however, the expression levels were gradually reduced. Continuous exposure for 72 h significantly repressed the expression of LdAgo2a and LdAgo2b in the first, second and third larval instars, and the four genes in final instars. Moreover, we found that ds LdSAHase -caused LdSAHase suppressions and larval mortalities were influenced by previous ds egfp exposure: 12 h of previous exposure increased LdSAHase silencing and mortality of the final instar larvae, whereas 72 h of exposure reduced LdSAHase silencing and mortality. Thus, it seems the activities of core RNAi-machinery proteins affect RNAi efficiency in L. decemlineata . [ABSTRACT FROM AUTHOR]

Background: Wilms' tumor (WT) is one of the most common malignant neoplasms of the urinary tract in children. Anaplastic histology (unfavorable histology) accounts for about 10% of whole WTs, and it is the single most important histologic predictor of treatment response and survival in patients with WT; however, until now the molecular basis of this phenotype is not very clearly. Methods: A real-time polymerase chain reaction (PCR) array was designed and tested. Next, the gene expression profile of pediatric anaplastic histology WT and normal adjacent tissues were analyzed. These expression data were anlyzed with Multi Experiment View (MEV) cluster software further. Datasets representing genes with altered expression profiles derived from cluster analyses were imported into the Ingenuity Pathway Analysis Tool (IPA). Results: 88 real-time PCR primer pairs for quantitative gene expression analysis of key genes involved in pediatric anaplastic histology WT were designed and tested. The gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal controls; we identified 15 genes that are up-regulated and 16 genes that are down-regulated in the former. To investigate biological interactions of these differently regulated genes, datasets representing genes with altered expression profiles were imported into the IPA for further analysis, which revealed three significant networks: Cancer, Hematological Disease, and Gene Expression, which included 27 focus molecules and a significance score of 43. The IPA analysis also grouped the differentially expressed genes into biological mechanisms related to Cell Death and Survival 1.15E-12, Cellular Development 2.84E-11, Cellular Growth and Proliferation 2.84E-11, Gene Expression 4.43E-10, and DNA Replication, Recombination, and Repair 1.39E-07. The important upstream regulators of pediatric anaplastic histology WT were TP53 and TGFβ1 signaling (P = 1.15E-14 and 3.79E-13, respectively). Conclusions: Our study demonstrates that the gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal tissues with real-time PCR array. We identified some genes that are dysregulated in pediatric anaplastic histology WT for the first time, such as HDAC7, and IPA analysis showed the most important pathways for pediatric anaplastic histology WT are TP53 and TGFβ1 signaling. This work may provide new clues into the molecular mechanisms behind pediatric anaplastic histology WT. [ABSTRACT FROM AUTHOR]

Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined. [ABSTRACT FROM AUTHOR]

Highlights: [•] The overexpression of the two RPK1 genes reduced the salt tolerance of A. thaliana. [•] The silencing of AtRPK1 gene expression enhanced the salt tolerance of A. thaliana. [•] The two RPK1 proteins are mainly distributed on the cell membrane. [•] The overexpression of RPK1 increased the membrane permeability and increased the Na+ fluxing into the cell. [•] The overexpression of RPK1 blocked the SOS signalling pathway and reduced the expression of P5CS1. [ABSTRACT FROM AUTHOR]

Abstract: The surface modification of Pigment Yellow 13, Pigment Red 254 and Pigment Blue 15 to improve their electrophoretic properties in electrophoretic suspension were studied. The particle size distribution and the surface morphology of the modified pigments were determined, the presence of the functional groups on the surface of pigments was confirmed, and the dispersion stability and chargeability of pigments suspended in electrophoretic slurry were characterized. For the application of microencapsulated electrophoretic displays, the colored microcapsules containing the modified organic pigments were prepared and spread on an ITO coated conducting film. A working prototype of electrophoretic display was successfully fabricated in this approach. [Copyright &y& Elsevier]

Abstract: Three novel lanthanide complexes, namely, [Ce(Himdc)(H2imdc)(H2O)3]·H2O (1), {[Dy(Himdc)(Ox)0.5(H2O)2]·H2O} n (2), and {[Nd(Himdc)(Ox)0.5(H2O)2]·H2O} n (3) (H3imdc=imidazole-4,5-dicarboxylic acid, Ox=oxalate), have been successfully prepared by the assembly of lanthanide ions and H3imdc ligand under different synthetic conditions. All of the complexes have been characterized by means of elemental analysis, IR, TG analysis, luminescence spectroscopy as well as single-crystal X-ray diffraction analysis. The 3D supramolecular structure of 1 is constructed from 1D zig-zag chains through the hydrogen bonding interactions. Complex 2 possesses the chair-shaped secondary building units (SBUs) with Dy6(Himdc)4(Ox)2 and meso-helical chains (P+M), resulting in a novel 2D structure based on the linkages of oxalate ligand. Complex 3 also presents 2D layer structure with uninodal 6-connected net topology, but crystallizes in the different space group and owns higher coordination number of the central metal atom than complex 2. The luminescence property of 2 is investigated in the solid state at room temperature. [Copyright &y& Elsevier]

Abstract: Interferon gamma (IFN-γ) is an immunomodulatory and anti-microbial cytokine, which has a variety of proatherogenic effects. It has been reported that IFN-γ can down-regulate ABCA1 expression. However, its mechanism is elusive. In the present study, we have investigated the effect of IFN-γ on ABCA1 expression and cholesterol efflux in THP-1 macrophage-derived foam cells. IFN-γ decreased ABCA1 expression at both transcriptional and translational levels in a dose-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by IFN-γ treatment. Liver X receptor α (LXRα), which can regulate the expression of ABCA1, was also down-regulated by IFN-γ treatment. LXRα-specific activation by LXRα agonist almost compensated the down-regulation of ABCA1 expression by IFN-γ, while siRNA of LXRα led to down-regulation of ABCA1 expression more significantly than IFN-γ. IFN-γ induced phosphorylation of STAT1 and expression of STAT1α in the nucleus, which was inhibited by a JAK inhibitor AG-490. Treatment with STAT1 siRNA further enhanced down-regulation of LXRα mRNA by IFN-γ. Furthermore, AG-490 and STAT1 siRNA almost compensated the effect of IFN-γ on ABCA1 expression and cholesterol efflux. In conclusion, IFN-γ may first down-regulate expression of LXRα through the JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study may be useful in understanding the critical effect of IFN-γ in pathogenesis of atherosclerosis. [Copyright &y& Elsevier]

Abstract: ABCA1 is a key mediator of cholesterol efflux to apoA-I in cholesterol loaded macrophages, a first step of RCT in vivo. Unsaturated fatty acids can inhibit cholesterol efflux from macrophages by increasing degradation of ABCA1. However, the detailed mechanisms of ABCA1 regulation by unsaturated fatty acids are not fully understood. In the present study, we investigated the effects of EPA on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of cAMP/PKA pathway on the regulation of ABCA1 by EPA in THP-1 macrophage-derived foam cells. Results showed that EPA significantly destabilized ABCA1 protein and reduced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 mRNA expression. We also revealed that EPA markedly reduced cAMP level and PKA activity and ABCA1 serine phosphorylation. PKA-specific activation by PKA agonist markedly compensated the down-regulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by EPA, while, siRNA of PKA leaded to reduce of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux more significantly than EPA. However, EPA-Induced enhancement of degradation rate of ABCA1 protein did not change by treatment with PKA agonist or PKA-siRNA. These results provide evidence that EPA may have dual negative effects on ABCA1 activity by decreasing ABCA1 protein level and by reducing PKA-mediated ABCA1 serine phosphorylation in THP-1 macrophage-derived foam cells. [Copyright &y& Elsevier]