Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors

Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.     

Design and characterization of novel β-cyclodextrin based copolymer materials

Reported herein are the systematic design and characterization of several novel polyurethane (PU) copolymers containing a macrocyclic porogen (β-cyclodextrin; β-CD). These copolymers were synthesized from the reaction between β-CD with different types of diisocyanate linker molecules (e.g., 1,6-hexamethylene diisocyanate (HDI), 4,4′-dicyclohexylmethane diisocyanate (CDI), 4,4′-diphenylmethane diisocyanate (MDI), 1,4-phenylene diisocyanate (PDI) and 1,5-naphthalene diisocyanate (NDI)) at variable synthetic conditions. The copolymers were characterized using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), solid state ¹³C CP-MAS NMR, ¹H/¹³C solution NMR spectroscopy, thermogravimetric analysis (TGA) and elemental analyses (CHN). The PU copolymers were generally insoluble in water and the optimal preparation of copolymer materials for sorption-based applications is for β-CD/linker synthetic mole ratios from 1:1 to 1:3. The practical upper limit of the crosslink density (∼1:7, β-CD/linker) depends on the steric bulk of the cross linker units.     

Do short courses in evidence based medicine improve knowledge and skills? Validation of Berlin questionnaire and before and after study of courses in evidence based medicine

ObjectiveTo develop and validate an instrument for measuring knowledge and skills in evidence based medicine and to investigate whether short courses in evidence based medicine lead to a meaningful increase in knowledge and skills.DesignDevelopment and validation of an assessment instrument and before and after study.SettingVarious postgraduate short courses in evidence based medicine in Germany.ParticipantsThe instrument was validated with experts in evidence based medicine, postgraduate doctors, and medical students. The effect of courses was assessed by postgraduate doctors from medical and surgical backgrounds.InterventionIntensive 3 day courses in evidence based medicine delivered through tutor facilitated small groups.ResultsThe questionnaire distinguished reliably between groups with different expertise in evidence based medicine. Experts attained a threefold higher average score than students. Postgraduates who had not attended a course performed better than students but significantly worse than experts. Knowledge and skills in evidence based medicine increased after the course by 57% (mean score before course 6.3 (SD 2.9) v 9.9 (SD 2.8), P<0.001). No difference was found among experts or students in absence of an intervention.ConclusionsThe instrument reliably assessed knowledge and skills in evidence based medicine. An intensive 3 day course in evidence based medicine led to a significant increase in knowledge and skills.

What is already known on this topic

Numerous observational studies have investigated the impact of teaching evidence based medicine to healthcare professionals, with conflicting resultsMost of the studies were of poor methodological quality

What this study adds

An instrument assessing basic knowledge and skills required for practising evidence based medicine was developed and validatedAn intensive 3 day course on evidence based medicine for doctors from various backgrounds and training level led to a clinically meaningful improvement of knowledge and skills     

Recycling‐mediated facilitation and coexistence based on plant size

We introduce nutrient recycling into a model where competitors differ in the scale at which they perceive their environment. In a two-resource system with both external nutrient inputs and recycling, larger consumers ("integrators") often generate resource distributions that favor their smaller ("nonintegrator") competitors, and vice versa. This occurs because recycling of integrator biomass reduces between-patch resource heterogeneity, whereas recycling of nonintegrator biomass does not. Combined, recycling and throughput can allow coexistence when it is not possible with either alone. With recycling, the presence of an integrator also may facilitate higher biomass of a co-occurring nonintegrator. Our model provides a context where recycling can generate negative feedback between competitors that differ in size and so promote coexistence. This is opposite to the positive recycling-mediated feedback commonly expected on the basis of litter chemistry differences between competitors. Effects of recycling and homogenization on nonintegrators may also be negative in our model, depending on the conformation of the system's resource supply points and the species' relative resource requirements. Our model suggests that the effects of plant size on competitive outcomes may depend critically on the degree of resource recycling found in the system and, reciprocally, that the effects of recycling may depend on plant size.     

Forecasting Helicoverpa populations in Australia： A comparison of regression based models and a bioclimatic based modelling approach

Abstract Long-term forecasts of pest pressure are central to the effective management of many agricultural insect pests. In the eastern cropping regions of Australia, serious infestations of Helicoverpa punctigera (Wallengren) and H. armigera (Hübner)(Lepidoptera: Noctuidae) are experienced annually. Regression analyses of a long series of light-trap catches of adult moths were used to describe the seasonal dynamics of both species. The size of the spring generation in eastern cropping zones could be related to rainfall in putative source areas in inland Australia. Subsequent generations could be related to the abundance of various crops in agricultural areas, rainfall and the magnitude of the spring population peak. As rainfall figured prominently as a predictor variable, and can itself be predicted using the Southern Oscillation Index (SOI), trap catches were also related to this variable. The geographic distribution of each species was modelled in relation to climate and CLIMEX was used to predict temporal variation in abundance at given putative source sites in inland Australia using historical meteorological data. These predictions were then correlated with subsequent pest abundance data in a major cropping region. The regression-based and bioclimatic-based approaches to predicting pest abundance are compared and their utility in predicting and interpreting pest dynamics are discussed.     

Systematic positions of Lamiophlomis and Paraphlomis （Lamiaceae） based on nuclear and chloroplast sequences

Genera Lamiophlomis and Paraphlomis were originally separated from genus Phlomis s.1. on the basis of particular morphological characteristics. However, their relationship was highly contentious, as evidenced by the literature. In the present paper, the systematic positions of Lamiophlomis, Paraphlomis, and their related genera were assessed based on nuclear internal transcribed spacer （ITS） and chloroplast rpl16 and trnL-F sequence data using maximum parsimony （MP） and Bayesian methods. and outgroup were sampled. Analyses of both separate In total, 24 species representing six genera of the ingroup and combined sequence data were conducted to resolve the systematic relationships of these genera. The results reveal that Lamiophlomis is nested within Phlomis sect. Phlomoides and its generic status is not supported. With the inclusion ofLamiophlomis rotata in sect. Phlomoides, sections Phlomis and Phlomoides of Phlomis were resolved as monophyletic. Paraphlomis was supported as an independent genus. However, the resolution of its monophyly conflicted between MP and Bayesian analyses, suggesting the need for expended sampling and further evidence.     

Potent and novel 11β-HSD1 inhibitors identified from shape and docking based virtual screening

Several potent and novel 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC(50) values lower than 100 nM and the best one 3.7 nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11β-HSD1 over 11β-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11β-HSD1 inhibitors to protect against metabolic syndrome.     

Predicting lncRNA–miRNA interactions based on interactome network and graphlet interaction

In the development and treatment of many human diseases, the regulatory roles between lncRNAs and miRNAs are important, but much remains unknown about them; moreover, experimental methods for analyzing them are expensive and time-consuming. In this work, we applied a semi-supervised interactome network-based approach to explore and forecast the latent interaction between lncRNAs and miRNAs. We constructed graphs according to the similarity of each of lncRNAs and miRNAs and determined the number of graphlet interaction isomers between nodes in these two graphs. According to the two graphs and the known interactive relationship, we calculated a score for lncRNA–miRNA pairs, as the prediction result. The results showed that the model (LMI-INGI) was reliable in fivefold cross-validation (AUC = 0.8957, PRE = 0.6815, REC = 0.8842, F1 score = 0.7452, AUPR = 0.9213). We also tested the model with data based on the similarity of expression profile and similarity of function for verifying the applicability of LMI-INGI, and the resulting AUC value was 0.9197 and 0.9006, respectively. Compared with the other four algorithms and variable similarity tests, our model successfully demonstrated superiority and good generalizability. LMI-INGI would be helpful in forecasting interactions between lncRNAs and miRNAs.     

Late Glacial and Holocene history of Plešné Lake and its surrounding landscape based on pollen and palaeoalgological analyses

Pollen analysis has been carried out on a 549 cm thick sediment profile from lake Ple?né jezero (Ple?né Lake) in the Bohemian Forest (?umava, Czech Republic; 1090 m a.s.l.; 48°47′ N; 13°52′ E). Analyses of 67 samples characterise the development of the lake biotope and the surrounding landscape during the last ca. 14,000 years. The pollen diagram shows a very distinct transition between the Late Glacial and the Holocene biostratigraphic units at a depth of ca. 312 cm. In the surroundings of Ple?né Lake the vegetation was treeless during the entire Late Glacial. The alpine tree limit, formed by Betula and Pinus with undergrowth of shrubs, might have been at ca. 500 m a.s.l. Pollen transported from long distances was significant due to the openness of the landscape, coming from southern Europe and even Africa, and including high numbers of Artemisia, Poaceae, Chenopodiaceae, and some other herbs and shrubs from steppe and forest-steppe areas in southern Europe or Africa (likely Ephedra, certainly Lygeum spartum). The expansion of shrubs, particularly Juniperus, preceded the expansion of trees near the end of the Late Glacial. Afforestation of the region by thin stands of Betula and Pinus occurred during the Preboreal. Significant warming in the Boreal resulted in the expansion of Corylus, Quercetum mixtum (QM) trees, and probably also Picea and Alnus. Picea as well as QM trees were further expanding during the Early Atlantic. Picea was the dominant tree during the Late Atlantic and Fagus started to spread towards its end. Abrupt expansion of Abies marks the Subboreal. A high degree of afforestation (Abies, Fagus, Picea) was characteristic for the Early Subatlantic. During Late Subatlantic, pollen of synanthropic plants appears. Phases of the lake biotope development were defined on the basis of coccal green algae and Isoëtes.     

Sequence‐ and activity‐based screening of microbial genomes for novel dehalogenases

Dehalogenases are environmentally important enzymes that detoxify organohalogens by cleaving their carbon-halogen bonds. Many microbial genomes harbour enzyme families containing dehalogenases, but a sequence-based identification of genuine dehalogenases with high confidence is challenging because of the low sequence conservation among these enzymes. Furthermore, these protein families harbour a rich diversity of other enzymes including esterases and phosphatases. Reliable sequence determinants are necessary to harness genome sequencing-efforts for accelerating the discovery of novel dehalogenases with improved or modified activities. In an attempt to extract dehalogenase sequence fingerprints, 103 uncharacterized potential dehalogenase candidates belonging to the α/β hydrolase (ABH) and haloacid dehalogenase-like hydrolase (HAD) superfamilies were screened for dehalogenase, esterase and phosphatase activity. In this first biochemical screen, 1 haloalkane dehalogenase, 1 fluoroacetate dehalogenase and 5 l -2-haloacid dehalogenases were found (success rate 7%), as well as 19 esterases and 31 phosphatases. Using this functional data, we refined the sequence-based dehalogenase selection criteria and applied them to a second functional screen, which identified novel dehalogenase activity in 13 out of only 24 proteins (54%), increasing the success rate eightfold. Four new l -2-haloacid dehalogenases from the HAD superfamily were found to hydrolyse fluoroacetate, an activity never previously ascribed to enzymes in this superfamily.     

Classification ofPythium ‘group F’ based on mycelial protein and isozyme patterns

Taxonomic characteristics were compared among 10 isolates ofPythium group F in tems of the electrophoretic patterns of their mycelial proteins and isozymes. These isolates were obtained from water of three ponds in different seasons and have an identical morphology of zoosporangia. Attempts to cross the isolates with each other themselves and with other isolates from the same group failed.Pythium group F is the most dominant of the pythia in the aquatic ecosystem and is difficult to identify because of the lack of sexual reproductive structures. Isozyme analysis proved useful in this respect. Comparisons of banding patterns of total soluble proteins and isozymes revealed five subgroups inPythium group F. Two isolates obtained from water of different ponds in different seasons showed the same protein and isozyme patterns. Our findings indicate that the use of total soluble protein and isozyme patterns for determining the variation withinPythium group F could become a valuable adjunct to the morphological and physiological criteria.     

Do marker‐based paternity assignments favour heterozygous and unrelated males?

Genetic marker‐based parentage analyses are widely applied to studies of natural populations in the fields of evolutionary biology, conservation biology and ecology. When the same markers used in a parentage analysis are used together with the inferred parentage in a downstream analysis, such as the analysis of mate choice in terms of heterozygosity or relatedness, a bias may be incurred because a subset of the genotypes are favoured in parentage assignments or non‐exclusions. A previous simulation study shows that exclusion‐based paternity analyses are biased in favour of heterozygous males, and males less related to the mothers than expected under random mating. In this study, I investigated the biases of genetic paternity analyses achieved by both exclusion‐ and likelihood‐based methods, using both analytical and simulation approaches. It is concluded that while both exclusion‐ and likelihood‐based methods can lead to biased paternity assignments or non‐exclusions in favour of a subset of genotypes, the bias is not consistently towards heterozygous males or males apparently less related to mothers. Both the direction and extent of the bias depend heavily on the allele frequency distribution and the number of markers, the methods used for paternity assignments, and the estimators of relatedness. There exist important differences in the patterns of the biases between exclusion‐ and likelihood‐based paternity analysis methods. It is concluded that the markers, except when they are highly informative to yield accurate paternity assignments or exclusions, should be split into two subsets which are used separately in the paternity and downstream analyses.     

Random selection—A simple model based on linear birth and death processes

Linear birth and death processes are used to derive simple expressions for sequential extinction times and gene fixation probabilities in asexual populations.     

Efficient shared memory and RDMA based collectives on multi-rail QsNetII SMP clusters

Clusters of Symmetric Multiprocessors (SMP) are more commonplace than ever in achieving high-performance. Scientific applications running on clusters employ collective communications extensively. Shared memory communication and Remote Direct Memory Access (RDMA) over multi-rail networks are promising approaches in addressing the increasing demand on intra-node and inter-node communications, and thereby in boosting the performance of collectives in emerging multi-core SMP clusters. In this regard, this paper designs and evaluates two classes of collective communication algorithms directly at the Elan user-level over multi-rail Quadrics QsNet^II with message striping: 1) RDMA-based traditional multi-port algorithms for gather, all-gather, and all-to-all collectives for medium to large messages, and 2) RDMA-based and SMP-aware multi-port all-gather algorithms for small to medium size messages. The multi-port RDMA-based Direct algorithm for gather and all-to-all collectives gain an improvement of up to 2.15 for 4 KB messages over elan_gather(), and up to 2.26 for 2 KB messages over elan_alltoall(), respectively. For the all-gather, our SMP-aware Bruck algorithm outperforms all other all-gather algorithms including elan_gather() for 512 B to 8 KB messages, with a 1.96 improvement factor for 4 KB messages. Our multi-port Direct all-gather is the best algorithm for 16 KB to 1 MB, and outperforms elan_gather() by a factor of 1.49 for 32 KB messages. Experimentation with real applications has shown up to 1.47 communication speedup can be achieved using the proposed all-gather algorithms.

Externalising moods and psychological states in a cloud based system to enhance a pet-robot and child’s interaction

Background

This PATRICIA research project is about using pet robots to reduce pain and anxiety in hospitalized children. The study began 2 years ago and it is believed that the advances made in this project are significant. Patients, parents, nurses, psychologists, and engineers have adopted the Pleo robot, a baby dinosaur robotic pet, which works in different ways to assist children during hospitalization.

Methods

Focus is spent on creating a wireless communication system with the Pleo in order to help the coordinator, who conducts therapy with the child, monitor, understand, and control Pleo’s behavior at any moment. This article reports how this technological function is being developed and tested.

Results

Wireless communication between the Pleo and an Android device is achieved. The developed Android app allows the user to obtain any state of the robot without stopping its interaction with the patient. Moreover, information is sent to a cloud, so that robot moods, states and interactions can be shared among different robots.

Conclusions

Pleo attachment was successful for more than 1 month, working with children in therapy, which makes the investment capable of positive therapeutic possibilities. This technical improvement in the Pleo addresses two key issues in social robotics: needing an enhanced response to maintain the attention and engagement of the child, and using the system as a platform to collect the states of the child’s progress for clinical purposes.

     

Characteristics of flux and gel layer on microfilter and non-woven fabric filter surface based on anoxic–aerobic MBRs

Non-woven fabric filter- (NWFF) and microfilter-MBR modules were made using 100?μm polypropylene and 0.25?μm polyethylene materials, respectively. The performances and mechanisms of the two processes were investigated, including additional batch filtration tests to find the function of the dynamic gel layer on the membrane surface. The HRT of both MBRs was 9?h and the operating permeate flux was 13?L/m(2)/h. The two MBRs consisted of an anoxic and aerobic reactor. The NWFF or microfilter (MF) was submerged in each of the aerobic reactors. The two MBRs showed similar performances for the removal of organic matters, suspended solids and nitrogen. Cake formation on the NWFF contributed to major resistance, while the gel layer on the microfilter or internal fouling of the pores played a key role in the fouling of the membrane surface. The amount of soluble extracellular polymer substances (EPS) (13?mg/L) of the attached sludge on the NWFF surface was larger than that (11?mg/L) of that suspended sludge. Consequently, the functional gel layer for the coarse and microfilter is established based on the relationship among the EPS, transmembrane pressure and MLSS.     

How accurate and statistically robust are catalytic site predictions based on closeness centrality?

Background  

We examine the accuracy of enzyme catalytic residue predictions from a network representation of protein structure. In this model, amino acid α-carbons specify vertices within a graph and edges connect vertices that are proximal in structure. Closeness centrality, which has shown promise in previous investigations, is used to identify important positions within the network. Closeness centrality, a global measure of network centrality, is calculated as the reciprocal of the average distance between vertex i and all other vertices.