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Wendy Warr (firstname.lastname@example.com) for the ACS CINF Chemical Information Bulletin
David Winkler, CSIRO Fellow, and professor at Latrobe Institute for Molecular Science, and Monash Institute of Pharmaceutical Sciences, Melbourne, Australia, received the 2017 Herman Skolnik Award for his seminal contributions to chemical information in the development of optimally sparse, robust machine learning methods for QSAR, and in leading the application of cheminformatics methods to biomaterials, nanomaterials, and regenerative medicine. A summary of his achievements has been published in the Chemical Information Bulletin. David was invited to present an award symposium at the Fall 2017 ACS National Meeting in Washington, DC. He invited six speakers:
L to R: Alex Tropsha, Johnny Gasteiger, Yoram Cohen; Tim Clark, David Winkler, Ceyda Oksel, Tudor Oprea
Tim Clark, of the University of Erlangen-Nürnberg, was the first speaker. The impact of modern hardware and software on simulations has not been an issue of doing things faster and faster, but rather one of doing calculations that we could not do before. Ab initio calculations can now be done on compounds with several hundred atoms, density functional theory calculations on a few thousand atoms, and semiempirical molecular orbital (MO) calculations on 100,000 atoms. Simulations of several microseconds are now standard.
Semiempirical (neglect of diatomic differential overlap, NDDO) molecular orbital (MO) calculations without local approximations are now possible for 100,000 atoms or more with the massively parallel semiEMPIRical molEcular-Orbital Program (EMPIRE) program,1-3 which is freely available to academic groups. Calculation scales with approximately N2.5. We are no longer limited to small or homogeneous, perfect systems, but can now include defects, dopants, impurities or domain boundaries in the calculations, or even calculate amorphous systems.
The results of such calculations can be used to simulate charge-transport through disordered monolayers. Clark's team has studied self-assembled monolayer field-effect transistors (SAMFETs) handling conformational freedom using classical atomistic molecular-dynamics (MD) simulations, electronic properties using very large scale semiempirical MO theory, and conductance by propagating single electrons or using diffusion quantum Monte-Carlo (DQMC) charge-transport simulations.4-9
The molecules that comprise the SAM contain insulating and semiconducting moieties, so that they serve as both gate dielectric and the active transistor channel in a device:
Tim's team has used simulations to describe and optimize complex systems of self-assembled monolayers on surfaces, not only to explain their morphology, but also to predict molecular compositions and arrangements favorable for improved charge transport.7 In more recent work,10 they have constructed transistors based on SAMs of two molecules that consist of the organic p-type semiconductor benzothieno[3,2-b][1]benzothiophene (BTBT), linked to a C11 or C12 alkylphosphonic acid. Both molecules form ordered SAMs, but the experiments show that the size of the crystalline domains and the charge-transport properties vary considerably in the two systems. Because of the angle of the head groups one can form crystalline domains and the other cannot. This can be reproduced with simple force field calculations.
The procedure for charge transfer simulations is as follows:
Tim showed an MD simulation of the charge transport paths. For the transport calculations, the team employed a fully quantum mechanical description, namely Landauer transport theory.9 In accord with experiment, they found an improved charge transport across BTBT-C11-PA SAMs compared to BTBT-C12-PA SAMs.
DQMC reproduces voltage/current curves (assuming that the number of Monte Carlo steps correlates with time) and reproduces experimentally observed hysteresis. It also revealed dimeric fullerene electron traps.15 Density functional theory calculations indicate that van der Waals fullerene oligomers can form interstitial electron traps in which the electrons are even more strongly bound than in isolated fullerene radical anions. Spectroelectrochemical measurements on a bis-fullerene-substituted peptide provide experimental support. The proposed deep electron traps are relevant for all organic electronics applications in which non-covalently linked fullerenes in van der Waals contact with one another serve as n-type semiconductors.
Finally Tim showed the results of simulations of hole-transport through a self-assembled monolayer substituted with a p-type organic semiconductor and with crystalline domains (see the work above on BTBT linked to a C11 or C12 alkylphosphonic acid). He illustrated hole transport through the monolayers. Hysteresis is not observed in this case. Tim also illustrated well-defined paths through the crystalline domains of the O2(OH)P(CH2)11-BTBT material. The researchers have shown that structural order is particularly important for the electronic properties of semiconducting self-assembled monolayers, and they predict that semiconducting SAMs with a higher degree of crystallinity and larger crystalline regions will exhibit superior performance.
Alex Tropsha, of the University of North Carolina Chapel Hill, UNC Eshelman School of Pharmacy, is benefiting from the explosive growth of materials data. There are 160,000 entries in the Inorganic Crystal Structure Database (ICSD). There are numerous commercial and open experimental databases (NIST, MatWeb, MatBase etc.), and huge databases such as AFLOWLIB, Materials Project, and Harvard Clean Energy. The chemical space of possible materials is huge : about 10100 candidates.16 The US government's Materials Genome Initiative recognizes the need for new high performance materials. The growth of materials databases and emerging informatics approaches offers the opportunity to transform materials discovery into data- and knowledge-driven rational design.
AFLOW is a globally available database of 1,688,245 material compounds, with over 167,136,255 calculated properties. The optimized geometries, symmetries, band structures, and densities of states available in the AFLOWLIB consortium databases have been converted into two distinct types of fingerprints: Band structure fingerprints (B- fingerprints), and Density of States fingerprints (D-fingerprints).17 The framework is employed to query large databases of materials using similarity concepts, to map the connectivity of materials space (as a materials cartogram) for rapidly identifying regions with unique organizations and properties, and to develop predictive quantitative materials structure−property relationship (QMSPR) models for guiding materials design.
To represent the library of materials as a network (a material cartogram), the researchers considered each material, encoded by its fingerprint, as a node. Edges exist between nodes with similarities above certain thresholds (in this case, Tanimoto similarity and a threshold of 0.7). A materials map from B-fingerprints was made from 15,000 materials from ICSD, using DFT PBE calculations from AFLOWLIB. Four big clusters were observed: insulators, ceramics, and complex oxides; bimetals and polymetals; metallic and nonmetallic combinations; and small band gap semiconductors.
Novel descriptors (property-labeled materials fragments) not requiring prior DFT calculations have also been developed by Voronoi tessellation and neighbors search of crystal structures, followed by infinite periodic graph construction and property labeling, and generation of circular fingerprints.18 Starting from only a crystal structure, regression models can be built to predict band gap energy, and thus electronic properties, or to predict thermo-mechanical properties such as bulk modulus, shear modulus, thermal expansion, heat capacity, and thermal conductivity. All the models are trained based on DFT-computed properties. Heuristic design rules can be extracted.
Material informatics has also been applied to the design of a novel photocathode material for dye-sensitized solar cells (DSSCs).19 By conducting a virtual screening of 50,000 known inorganic compounds, the researchers have identified lead titanate (PbTiO3), as the most promising photocathode material. Notably, lead titanate is significantly different from the traditional base elements or crystal structures used for photocathodes. In experimental validation, the fabricated lead titanate DSSC devices exhibited the best performance in aqueous solution, showing remarkably high fill factors compared to typical photocathode systems. Currently, device performance is low, but it might be improved by designing a new dye.
Next Alex discussed applications of machine learning to designing chemicals with the desired physical and biological properties where compound structure is described only by its SMILES notation, and no other conventional chemical descriptors are used. The new approach developed in his lab is based on concepts from text mining that rely on neural networks to solve the problem of semantic similarity of texts.
The British linguist J. R. Firth is noted for drawing attention to the context-dependent nature of meaning. In particular, he is known for the 1957 quotation: "You shall know a word by the company it keeps". To define the semantic similarity between two entities, Alex and his colleagues have made use of approaches embedded in Word2Vec, a neural-network-based approach to describe linguistic context of words developed at Google.20 With Word2Vec, a network is trained using each word of a corpus of text and some configurable number of surrounding words. The model can be trained to either predict the surrounding context based on the current word, or to predict the current word from the context. Elena Tutubalina and Alex (manuscript in preparation) have performed drug clustering in semantic similarity space, using webmd.com, patient.info, drugs.com, amazon.com, askapatient.com, and dailystrength.org as sources of user comments, and showed that drugs with similar pharmaceutical action do cluster together in the semantic similarity space.
Alex's team has also experimented with de novo design of molecules with the desired properties using SMILES in Deep Reinforcement Learning:
Structural bias, physical properties, and biological activity have been used in proof of concept case studies of user-biased molecular design. In summary, Alex cited Confucius who said, "Without knowing the force of words, it is impossible to know more". Alex quipped "And remember: anything you say can, and will be used … for text mining!".
Yoram Cohen of the University of California Center for Environmental Implications of Nanotechnology gave a talk co-authored by colleagues at the University of California. Nanoinfo.org is a nanoinformatics platform that supports the environmental impact assessment of engineered nanomaterials (ENMs) with a central database of ENM safety data and a toolkit for various exploration and analysis methods.21 These methods include the estimation of environmental exposure levels of ENMs (MendNano), evaluation of environmental releases of ENMs (LearNano), analysis of high throughput toxicity data of ENMs (ToxNano), and predictive toxicity models, and analysis of the environmental impact of ENMs via Bayesian inference (NanoEIA).
NanoDatabank is a data repository of ENM properties, and experimental and simulation datasets of ENM toxicity and environmental fate and transport (F&T). It contains databases that include physicochemical properties; toxicological properties; experimental datasets of ENM toxicity and F&T; and results of model simulations and estimation of ENM toxicity and F&T behavior, and physicochemical properties. It includes data for over 300 nanomaterials, and toxicity data for various cell lines, zebrafish and bacterial strains, from 325 publications. ToxNano is a high-content data analysis tool (HDAT)22,23 offering QSARs using random forest and Bayesian network toxicity models; analysis of knowledge evidence, and data visualization. MendNano (multimedia environmental distribution of nanomaterials) is a Web-based modeling platform.24,25 Nanoinf.org has 400 users from more than 50 countries.
As an example of work on the toxicity of nanomaterials, Yoram presented unpublished results on evaluating the body of evidence on quantum dots (QDs) via meta-analysis. QDs are very small semiconductor particles, only several nanometers in size, so small that their optical and electronic properties differ from those of larger particles. Many types of quantum dot will emit light of specific frequencies if electricity or light is applied to them, and these frequencies can be precisely tuned by changing the dots' size, shape, and material.
QD data were collected from 448 publications, reporting 2,703 samples, with 7 core types, 12 shell types, 13 surface modifications, 14 surface ligands, and 20 assay types. In the predictive toxicity model R2 was about 0.81 for cell viability, and about 0.83 for IC50. Yoram and his colleagues studied cause-effect relationships between cellular bioactivity and QD attributes. Median IC50 was ≤ 10 mg/L, for the surface ligands of type amphiphilic polymer, lipid, other hydrophobic, aminothiol, and other amphiphilic. It was uniformly distributed for silica. There was no correlation between surface charge and IC50. The sensitivity distribution of IC50 for cell anatomical type suggests that more differentiated cells are more adversely affected by exposure to QDs. Toxicity is not governed by QD size alone: there is a wide range of IC50 for a given size, and toxicity can be high or low irrespective of the size. Core type affects toxicity, but the wide range of IC50 for a given core type suggests that there are other important attributes.
Bayesian network models can be useful for handling uncertainties, mixed attributes, and hidden conditional relationships since they provide rigorous and simple mathematical means of handling data uncertainty; they integrate graphical representation of the problem with probabilistic evaluation of variable relationships; they can incorporate prior knowledge based on data as well as expert opinion in a convenient representation of probability distributions; and they calculate the likelihood of specific scenarios based on prior knowledge.
Bayesian network model sensitivity analysis showed that QD toxicity is correlated with the most relevant (or significant) attributes tabulated below. The QD attributes identified in this study were consistent with previous analysis via random forest.26
|Bayesian network for IC50
|Random forest for IC50
|Surface ligand
|QD diameter
|Surface ligand
|QD diameter
|Assay type
|Assay type
|Exposure time
|Exposure time
|Surface modification
|Surface modification
|Surface charge
|Surface charge
|Bayesian network for cell viability
|Random forest for cell viability
|Surface ligand
|QD diameter
|QD diameter
|QD concentration
|QD concentration
|Surface ligand
|Exposure time
|Exposure time
|Surface modification
|Assay type
|Assay type
|Surface modification
|Surface charge
|Surface charge
Bayesian networks for new explorations of association rules among various biological responses as a result of exposure to manufactured nanomaterials have also been demonstrated in zebrafish toxicity studies. Yoram and his co-workers used a nanomaterial biological interaction knowledge base of zebrafish phenotype data with 1,147 samples, and 11 biological responses (including mortality). The data included exposure to seven material types (carbon, cellulose, dendrimer, metal, (metal) oxide, polymeric, and semiconductor) of 0.8–250 nm average primary size; concentration; number of embryos per experiment; and responses recorded for each exposure scenario.
The Bayesian network model for zebrafish mortality (percentage of dead embryos) had an R2 of about 0.79. Sensitivity analysis of the key material properties and exposure conditions that correlate with zebrafish mortality was carried out, and cause-effect relationships between zebrafish phenotypes and material properties and exposure conditions were investigated. Attribute significance was determined by exhaustive search of 13 attributes using bootstrapping. Mortality at 120 hours post-fertilization correlated with concentration used, core atomic composition, outermost surface, average particle size, surface charge, shell composition and purity. The significant attributes at 24 hours post-fertilization were the same but the ranking of the top four differed slightly.
The responsible development of beneficial manufactured nanomaterials requires a thorough understanding of their potential adverse environmental and human health impacts. This requires predicting the biological response of various receptors when exposed to these materials, along with an understanding of their fate and transport, and their range of likely exposure concentrations. Yoram's work helps to rank various nanomaterials with respect to their potential environmental impact.
Ceyda Oksel of Imperial College London reported on the PhD work27 she had done at the University of Leeds in collaboration with Xue Wang and David Winkler. Given the ever-increasing use of ENMs, it is essential to assess properly all potential risks that may occur as a result of exposure to ENMs. The distinctive characteristics of ENMs that have made them superior to bulk materials for particular applications might also have a substantial impact on the level of risk they pose. Despite the clear benefits that nanotechnology can bring, there are serious concerns about the potential health risks associated with the production and use of ENMs, intensified by the limited understanding of what makes ENMs toxic and how to make them safe.
The involvement of computational specialists in nano-safety research has become more prominent since Registration, Evaluation, Authorization and restriction of CHemicals (the European Union's REACH regulation) promoted the use of in silico techniques such as QSAR for toxicity assessment. Data-driven models that decode the relationships between the biological activities of ENMs and their physicochemical characteristics provide an attractive means of maximizing the value of scarce, and expensive, experimental nanotoxicity data.
Nano-QSAR models can be used to predict the properties of new materials and to design safer materials. Leeds-based genetic programming-based decision tree (GPTree) approach27 applies decision tree learning algorithms to identify the best combination of physicochemical properties to predict biological activity of ENMs. The trees are automatically constructed from the data. Decision trees have several advantages. They are able to deal with small, large and noisy datasets; they can detect nonlinear relationships (as well as linear ones); they allow input variables to be selected automatically; they are transparent; and they represent knowledge clearly (i.e., the models are interpretable).
GPTree begins with a random population of solutions and repeatedly attempts to find better solutions by applying genetic operators such as mutation and crossover. The first step is to construct a user-specified number of trees (usually a large number) starting from a random compound and a randomly chosen descriptor. Once the initial population is generated, tournament selection is performed to identify the best tree to be used as a parent tree for genetic operators such as crossover. The best tree from the subset of trees is chosen by its fitness (e.g., accuracy). Genetic operators such as crossover and mutation are used to form the next generation of trees that are added or replace the current generation. These steps are repeated until the user-specified number of generations has been created. The decision tree model with the highest accuracy of classification for the training set is selected as the optimal decision tree model.
Ceyda demonstrated the application of genetic-programming-based decision tree construction algorithms to QSAR modeling of ENM toxicity by five case studies. The accuracy of the model predictions was satisfactorily high and clearly highly statistically significant relative to the classification rate due to chance.
In the first case study, a large set of in-house in vitro data (obtained in collaboration with Edinburgh University) was used. The dataset included a panel of 18 ENMs with varying structures (e.g., carbon-based materials and metal oxides), a set of in vitro cytotoxicity assays (e.g., LDH release, apoptosis, necrosis, viability, MTT and hemolytic effects), and several experimentally measured physicochemical properties (e.g., particle size and size distribution, surface area, morphology, metal content, reactivity and free radical generation). After a set of data preparation and scaling steps, a heat map of toxicity data combined with hierarchical clustering was constructed. As a second step, C-Visual Explorer (CVE) was used as a tool to create a parallel coordinate plot of the multivariate toxicity data. Similar to the heat map visualization results, the parallel coordinate plot showed that the aminated polystyrene latex beads and zinc oxide had the highest toxicity values in nearly all assays, followed by nanotubes that had medium to high toxicity values in viability and MTT assays.
Then, a dimensionality reduction technique, principal component analysis, was performed on all the toxicity data and the ENMs were divided into five categories according to their toxicity values. GPTree was used to identify potential descriptors contributing to the toxicity of four particular ENMs that were clearly separated from the main cluster formed by low-toxicity ENMs. It was concluded that high aspect ratio contributed to the toxicity of nanotubes, while the most likely factor driving the toxicity of zinc oxide was its high zinc content.
In the second case study, the cellular uptake of nanoparticles, 13 descriptors representing the hydrogen-bonding characteristics, functional group counts, molecular shape, composition and polarizability were found to be significant among a larger set of 147 chemically interpretable descriptors. The findings of GPTree analysis regarding the large contribution of lipophilicity, hydrogen bonding and molecular shape descriptors in the cellular uptake behavior of nanoparticles is consistent with earlier studies.
For a cytotoxicity to human keratinocytes dataset (the third case study),28 the descriptors selected by GPTree were the enthalpy of formation of metal oxide nanocluster representing a fragment of the surface (), the Mulliken's electronegativity of the cluster, Xc, and the chemical hardness, η. The former two descriptors are consistent with the properties reported to be important for cytotoxicity of metal oxide nanoparticles. In addition, the chemical hardness corresponding to the reactivity was found to be an influential parameter on the cytotoxicity of nanoparticles.
The descriptors selected by GPTree were used to develop a regression model which was statistically significant and had good predictivity (R2 = 0.92, Q2 = 0.72). A variable importance plot showed that Xc was twice as important as , which was a little more important than η.
The data used in the fourth case study included a set of 27 descriptors, 23 ENMs, and a set of multi- and single-parameter toxicity screening assays. The descriptors selected by the GPTree model included nanoparticle conduction band energy, EC, and ionic index of metal cation, Z2/r. This finding is very consistent with past studies that identified these two descriptors as being important for the toxicity of metal oxide nanoparticles.
In the last case study, exocytosis of gold nanoparticles in macrophages, the optimal descriptors for predicting the exocytosis were the charge accumulation, zeta potential and charge density. These findings are in line with previous studies revealing an association between surface characteristics of gold nanoparticles, especially high positive surface charge, and their exocytosis patterns in macrophages.
Ceyda concludes that the genetic-programming-based decision tree construction algorithm shows considerable promise in its ability to identify the relationship between molecular descriptors and biological effects of ENMs. Selected decision tree models yielded (external) prediction accuracies of 86-100%. Another statistical test (Y-randomization) was also performed to demonstrate the robustness of the selected models. This work is a first step in the implementation of a genetic programming based decision tree construction algorithm to nano-QSAR studies.
Johnny Gasteiger of the University of Erlangen-Nürnberg is skeptical about deep neural networks: they are good for getting funding, but they are yet to be proven. Johnny illustrated some of the useful applications of shallow neural networks. Much like the human brain generates two-dimensional sensory maps of the environment, a Kohonen network (a self-organizing map) can generate two-dimensional maps of high-dimensional chemical data. Crucial for the success of the study of chemical problems by a self-organizing neural network is the representation of the chemical data.
The shape and surface of molecules are very important: the entire electrostatic potential can be seen in a colored 3D model. Johnny has projected the 3D Cartesian coordinates of, for example, 2-chloro-4-hydroxy-2-methylbutane onto a Kohonen net to get a 2D map:
The neurotransmitter acetylcholine binds to two types of receptors, the muscarinic and the nicotinic receptor. Kohonen maps of the van der Waals surface of muscarinic agonists (muscarine, atropine, scopolamine, pilocarpine) and nicotinic agonists (nicotine, (+)-anatoxin a, mecamylamine, pempidine) have also been produced by projecting points of the 3D surface on a 2D space.29 Such maps allowed the total molecular electrostatic potential (MEP) of a compound to be represented in a single picture, instead of requiring a series of pictures as formerly. Johnny showed the maps of the MEPs of the eight compounds with muscarinic agonists in the top row and nicotinic agonists below.
The results showed that the MEP is important for the binding of these compounds to their receptors. The Kohonen maps reflect significant characteristics of the MEPs and can therefore be used in the search for biologically active compounds.
In analytical chemistry, neural networks have been used in the classification of Italian olive oils.30 The classification was performed on a set of 572 Italian olive oils, from nine different regions, on the basis of an analysis of eight fatty acids. Kohonen learning was superior to a network using the back-propagation of errors. There were 250 oils in the training set and 322 in the test set; 312 of the 322 were correctly predicted. The nine Italian regions were nicely differentiated in the Kohonen map. What is, however, even more interesting is that the Kohonen map is reflecting the map of Italy. This emphasizes the power of unsupervised learning, discovering information that is hidden in the data. In this case, clearly, the different climates and the different soils are responsible for the separation of the regions of Italy in the self-organizing map:
Kohonen networks use unsupervised learning. Johnny next discussed examples of supervised learning. In one experiment the electronic properties located on the atoms of a molecule such as partial atomic charge, and electronegativity and polarizability values were encoded by an autocorrelation vector accounting for the constitution of a molecule.31 Using the 49-dimensional vector of seven properties and seven distances, it is possible to distinguish between 112 dopamine agonists and 60 benzodiazepine receptor agonists even after projection into a Kohonen map. The two types of compounds can still be distinguished if they are buried in a dataset of 8,323 compounds of a chemical supplier catalog comprising a wide structural variety. The method can be used for searching for structural similarity, and, in particular, for finding new lead structures with biological activity.
Gasteiger's team has also worked on simulation of infrared spectra.32 They developed an empirical approach to the modeling of the relationships between the 3D structure of a molecule and its IR spectrum based on a novel 3D structure representation, and a counterpropagation (CPG) neural network. The 3D coordinates of the atoms of a molecule are transformed into a structure code that has a fixed number of descriptors irrespective of the size of a molecule. The structure coding technique is referred to as radial distribution function (RDF) code.33 3D structures were transformed into radial codes (128 values) and put into a CPG network. IR spectra (128 absorbance values) were also input, and the network was trained. When IR spectra are simulated the fingerprint region is predicted well because of the representation of the 3D structure. A CPG network can be operated in reverse mode,33 enabling the prediction of a structure code. The input of a query infrared spectrum into a trained CPG network provides a structure code vector, which represents the radial distribution function with 128 discrete values. This RDF code is then decoded to provide the Cartesian coordinates of a 3D structure.
Johnny concluded by mentioning his recent collaboration with David Winkler on dye solubility in carbon dioxide.34 David has also worked on melting points of ionic liquids, fibrinogen adsorption to polymeric surfaces, and normalized metabolic activity of polymeric biomaterials. Johnny encouraged David to continue to do good science.
Tudor Oprea of the University of New Mexico believes that identifying novel targets as a precompetitive endeavor can lead to new therapeutic opportunities if academia and industry work together. Most protein classification schemes are based on structural and functional criteria. For therapeutic development, it is useful to understand how many data and what types of data are available for a given protein, thereby highlighting well-studied and understudied targets. Tudor and his co-workers classify proteins annotated as drug targets as "Tclin"; proteins for which potent small molecules are known as "Tchem"; proteins for which biology is better understood as "Tbio"; and proteins that lack antibodies, publications or National Center for Biotechnology Information (NCBI) Gene References Into Function (GeneRIFs) as "Tdark".
Tclin proteins are associated with drug mechanism of action (MoA). Tchem proteins have bioactivities in ChEMBL and DrugCentral, plus human curation for some targets. A Tbio protein lacks small molecule annotation, and is above the cutoff criteria for Tdark, or is annotated with a Gene Ontology (GO) molecular function or biological process leaf term(s) with an experimental evidence code, or has confirmed Online Mendelian Inheritance in Man (OMIM) phenotype(s). Tudor and his colleagues used name entity recognition software35 from L. J. Jensen's lab to evaluate nearly 27 million abstracts to derive a publication score per protein. Tdark proteins ("understudied proteins") have little information available, and meet two of the following three criteria: a PubMed text mining score of less than five, three or fewer GeneRIFs, and 50 or fewer antibodies available according to antibodypedia. As external validation, Tdark proteins have statistically significantly lower values compared to the other three target development levels (TDLs) in terms of fewer GO terms, fewer patents, fewer National Institutes of Health (NIH) R01 grants, and fewer searches of the STRING-db database.
Tudor's first "take home message" was that there is a knowledge deficit: over 37% of the proteins remain understudied (the Tdark ones) and only about 10% of the proteome (Tclin and Tchem) can be targeted by potent small molecules. Are Tdark proteins underfunded because there is no scientific interest in this category, or is the lack of knowledge perpetuated by lack of funding? It is possible that the absence of high-quality, well-characterized molecular tools (i.e., antibodies or chemical probes) may be a root cause for this situation, but lack of tools leads to lack of interest, and lack of interest diminishes the probability of such tools being developed.
The patent literature is also of interest. Almost half of patent bioactivity data are never published elsewhere, and compounds may appear in patents two to four years before they appear in the literature. The SureChEMBL team has annotated the SureChEMBL patent corpus with gene and disease terms. Looking at patents between 2001 and 2013, they processed a set of 99 approved patents of interest to the Illuminating the Druggable Genome (IDG) consortium. These bioactivity data from 99 patents were manually extracted: 20,941 activity measurements for 11,358 compounds, and 1,134 assays. These data are already uploaded into ChEMBL 23. Data for seven IDG Phase 2 targets were uncovered by this patent data extraction exercise, data which progress TDLs of two targets (GPR6 and HCAR1) from Tbio to Tchem.
Anne Hersey of ChEMBL has estimated that more than 50% of the data from patents do not end up in peer-reviewed papers. IDG, Open Targets, BindingDB, and others could collectively, in a precompetitive manner, mine data from patents (if necessary, for only terminated projects, or out-of-patent drugs) and upload these data into ChEMBL and Pharos. Pharos36 is the user interface to the Knowledge Management Center (KMC) for the IDG program funded by the NIH.
Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided insight into gene function and congenital disorders. The International Mouse Phenotyping Consortium (IMPC) has published research on the high-throughput discovery of novel developmental phenotypes.37 They identified 2,788 genes with 8,241 significant phenotype calls in 25 major categories. The promise of the IMPC annotations is illustrated by examining the definite and clear links between human neurological and behavioral disorders (191 human genes) and the corresponding gene knockout mouse neurological and behavioral phenotypes. The majority of these links are for schizophrenia, Alzheimer's disease, epilepsy, and amyotrophic lateral sclerosis. Several rare diseases are also associated with these genes.
Of 119 Tdark genes prioritized by KMC to IMPC, 45 mouse lines were produced, with 41 phenotypes observed. Knockouts of the Tdark kinase Alpk3 have increased embryonic and perinatal lethality, with the surviving adults displaying severe heart defects. Of 482 Tbio genes submitted by KMC, 184 mouse lines were produced, with 145 phenotypes observed. Knockouts of the Tbio GPCR Adgrd1 display reproductive defects. (These are Tdark and Tbio statistics as of April 2017.) Tudor commented: "If you don't know very much to begin with, don't expect to learn a lot quickly."
Data from Cristian Bologa suggest that on average it takes 15-20 years for Tdark to bear fruit. The leptin receptor was Tdark in 1995, but led to an approved drug in 2014. The smoothened receptor was Tdark in 1997, and a drug was launched in 2012. Tudor gave several other examples. There is room for improvement in research funding. Text mining of all NIH grants for the period 2000-2015 suggests that 8,858 proteins received zero NIH funding. Of these, 6,051 are Tdark, and 2,616 are Tbio. This is to be expected, but 119 are Tchem and 72 are Tclin. Possible explanations could be old drug targets or research funded elsewhere. (Data from funding sources other than NIH are not available.) Pharma and academia could pay more attention to these 8,858 underfunded proteins.
Tudor's second take home message was that just because something is ignored it does not mean it lacks importance. Understudied proteins need funding and patience. Based on current evidence, IMPC has the most concerted Tdark exploration approach.
DrugCentral (http://drugcentral.org ) is an open access online drug compendium38 integrating structure, bioactivity, regulatory information, pharmacologic actions, and indications for active pharmaceutical ingredients approved by regulatory agencies. It integrates content for active ingredients with pharmaceutical formulations, indexing drugs and drug label annotations, and complementing similar resources available online. Tudor's team used it initially to find how many drugs there are, but they also wanted to know how many drug targets there are. They have studied innovation patterns per therapeutic area:39
Drugs distributed by Anatomical Therapeutic Chemical (ATC) codes (levels 1-2). Concentric rings indicate ATC levels. Histograms represent the number of drugs distributed per year of first approval.
They have also examined the commercial impact of target classes by evaluating data from IMS Health on drug sales from 75 countries, aggregated over a five-year period (2011–2015). After excluding categories such as homeopathic medicines, they identified 51,095 unique products, and mapped them to 1,069 active pharmaceutical ingredients from DrugCentral, corrected by the number of active pharmaceutical ingredients (APIs) per product, then by the number of Tclin targets per API. The most lucrative target class from a therapeutic perspective was G-protein coupled receptors (GPCR, 27.42% market share). Tudor also tabulated the top 20 targets by revenue. His third take home message was that there are many unexplored opportunities. By his conservative estimate (about 15,000 disease concepts, and about 2500 unique drug indications), we address about 15% of human diseases with therapeutic agents.
It has been said that the absence of a quantitative language is the flaw of biological research40 or "the more facts we learn the less we understand". Again, when little is known, we should not expect knowledge to accumulate quickly. Separation by organ and cell is a conceptual fallacy. Medicine maintains this separation for necessity: by organ (e.g., cardiology or ophthalmology), and by disease category (e.g., oncology or infection). NIH Institutes are organized in a similar way. Many pharmaceutical companies are organized by therapeutic area. Yet genes, proteins and pathways do not observe such separation. The impact of this "mental divide" in science has yet to be understood.
A. B. Jensen et al. have studied disease correlations and temporal disease progression (trajectories)41 on a large scale over 15 years, and grouped 1,171 significant trajectories into temporal patterns centered on a small number of early diagnoses that are central to disease progression. Hence it is important to focus on early diagnoses in order to mitigate the risk of adverse patient outcomes. The authors suggest such trajectory analyses may be useful for predicting and preventing future diseases of individual patients. Using data from the Cerner HealthFacts database, Tudor's team has found that the top diseases prior to Alzheimer's (over 5 years or more) are essential hypertension, hyperlipidemia, Type 2 diabetes mellitus, hypercholesterolemia, and coronary atherosclerosis. For renal failure, diseases over the previous five years are essential hypertension, heart failure, angina pectoris, chronic heart disease, and diabetes mellitus.
Diseases are concepts. They lack physical manifestation outside patients, so the search for cures has to be patient-centered.42 Animal models should be combined with mining of patient data. We ought to use electronic health record data to prioritize targets for further drug discovery. For example, we should get genes associated with diseases that precede Alzheimer's to investigate possible causality. Such priorities could be disease-specific, or phenotype-specific.
It is time to acknowledge that target prioritization for drug discovery is precompetitive knowledge. The pharmaceutical industry reward system is based on patents, which are awarded for drugs, not targets. Finding a good target leads to the "me-too" phenomenon. It is time to pool resources together on targets, team up with Open Targets and create a Target Selection Consortium, partnering industry with academia. "Double blind" studies could be cosponsored, to avoid the reproducibility crisis. IDG KMC is seeking new knowledge.
David Winkler's award address was co-authored by his colleague Frank Burden, now retired from CSIRO, and by co-workers at Imperial College London, King's College London, and the University of Nottingham, whose work is acknowledged in the literature references.
David's research concerns computational chemistry applied to a molecular level understanding of interactions of molecules and materials with biology. He has a strong interdisciplinary, translational research focus. His modeling, design, and optimization of bioactive materials focus on testing model predictions by subsequent experiments. He employs a range of computational tools including quantum chemistry, molecular dynamics and mechanics, molecular graphics, pharmacophore models, protein docking, and, in the case of this talk, quantitative structure-property relationship modeling. He is interested in the design of drugs and materials for therapeutic and regenerative medicine, especially control of stem cell fate, with a particular focus on the application of artificial intelligence (AI), machine learning, pattern recognition, complex systems science, evolutionary algorithms, and adaptive learning.
His work has had commercial impact, including the transfer of neural network modeling technology to BioRAD Corporation; several field trials candidates with Du Pont and Schering Plough; and clinical trials of a radioprotectant drug for cancer radiotherapy patients (with Sirtex and the Peter Mac Cancer Institute). He developed core intellectual property (a novel antibacterial target in bacterial replisome) for the Betabiotics company spinoff, and discovered a new mechanism for strontium biomaterial-induced differentiation of mesenchymal stem cells to bone. He carried out a large project with Air Liquide Santé on using in silico methods to understand the surprisingly rich biological properties of noble gases. He discovered new antifibrotic and antihypertensive agents for Vectus Biosystems (allowing them to float on the stock market) and a first in class drug lead for myelofibrosis, which will be further developed by a new spin off company soon.
Winkler's research thinking was greatly influenced by complex systems science, which finds deep mechanistic similarities between areas of science that appear to have nothing in common. Concepts include nonlinear dynamical behavior, networks and their attractor states, self-organized criticality, chaos, and emergent properties. Complex systems science stimulates substantial lateral thinking and novel problem solving. Methods from other areas of science can provide novel solutions to problems in drug discovery; and methods developed for drug discovery can provide novel solutions to problems in other areas of science, such as biomaterials, gene expression, non-biological materials, and regenerative medicine.
QSAR was invented by Toshio Fujita (very recently deceased) and Corwin Hansch, and rapidly evolved into a method for optimization of drugs and agrochemicals. David and Toshio published a recent paper43 on the two forms of QSAR: "explain" and "predict". Graham Richards' and Peter Andrews' seminal commercialization ventures influenced David to make translation a strong focus in his research.
The research for which David received the Skolnik award involved the application of modern computational and mathematical methods to optimizing the QSAR modeling process.44 The first operation is to generate descriptors. Model quality is critically dependent on descriptors. Descriptors with low or no relevance to the property modeled degrade the model. Bad descriptors were a problem in early QSAR work, and there is still a major research need for good descriptors for materials. Next a subset of descriptors is chosen for the model in a context-dependent way. Choosing too many subsets can give chance correlations. In generating the relationship between the descriptors and the target property, model quality is less dependent on the modeling algorithm than on the descriptors, but there can be issues in overfitting, overtraining, ambiguity in network architecture, and subjective choices. The next operation is validating the performance of the model in predicting properties of new data. Here, cross validation and bootstrapping generate optimistic measures of performance, and an independent test set not used in training is best. The final operation is making new predictions from the model and synthesizing and testing new materials.
Descriptors are the last major research problem for QSAR. Many (such as DRAGON descriptors) are arcane; efficient, interpretable descriptors are needed. Descriptors specific to complex materials are essential, but the field is embryonic. High throughput characterization data can augment computed descriptors.
There are advantages in removing irrelevant features. Least squares in multiple linear regression (MLR) has a Gaussian prior. This can be replaced with a Laplacian prior which effects the removal of uninformative weights by driving them to zero. Sparse Bayesian feature selection methods (feature selection using expectation maximization) identify a small number of relevant features very efficiently.45
There are many methods of varying sophistication in finding structure-activity relationships,44 including simple linear statistical regression methods such as multiple linear regression; nonlinear regression methods using polynomials or nonlinear kernels, and nonlinear machine learning; bioinspired methods such as neural nets; support vector machines; and random forests. These have new applications in materials, nanotechnology, and regenerative medicine.
The universal approximation theorem states that neural networks can model any complex relationship given sufficient training data. Neural networks are very well suited to modeling of complex data, but they have problems such as overfitting and overtraining. They raise an ill-posed problem in statistics (instability), and optimum network architecture is ambiguous. The contribution of David and his co-workers is to develop very robust, self-optimizing sparse feature selection and neural network methods that overcome all these problems.46 These methods have been shown to have performance similar to that of deep neural networks.
Sparse Bayesian modeling and feature selection, replacing the Gaussian prior with the Laplacian prior, is a general nonlinear modeling method45,47-49 that automatically optimizes model complexity, prunes neural network weights to avoid overfitting, and prunes irrelevant descriptors to optimize the predictivity of a model. A sparsity-inducing Laplacian prior (LP) was introduced into Winkler's Bayesian Regularized Artificial Neural Network algorithm (BRANN) creating BRANNLP.47,49 Low relevance weights are set to zero, and descriptors are also pruned from the model if all weights are zero.
From selection and mapping, David turned to validation. Cross validation, bootstrapping, and other methods give an overly optimistic estimate of predictive power because the test set is not independent of the training set. An independent test set never seen by the model is the gold standard. Many measures of predictivity have been proposed. Test set validation is actually a simple problem in statistics; standard error of prediction, test set (SEP) is preferred over r2 as it is less dependent on dataset size and model complexity.46,50
Methods from other areas of science can provide novel solutions to problems in drug discovery, and methods developed for drug discovery can provide novel solutions to problems in other areas of science. Implantable medical devices are an example. Bacterial adhesion and growth on biomaterial surfaces of joint prostheses, heart valves, shunts, vascular and urinary catheters, and intraocular lenses are serious problems in health care. There is a major unmet medical need for new coating materials for implantable and indwelling medical devices. David and his co-workers from Morgan Alexander's research team at the University of Nottingham have used machine learning methods to derive quantitative models relating the molecular structure of a polymer to the attachment of the bacteria to that polymer surface. These models can be used to screen large databases of new materials for those with low pathogen attachment.
Hook et al. have detected the attachment of selected bacterial species to 576 polymeric materials in a high-throughput microarray format.51 In work by David and his colleagues, data from a large polymer microarray exposed to three clinical pathogens were used to derive robust and predictive machine learning models of pathogen attachment.52 The BRANN models can predict pathogen attachment for the polymer library quantitatively. The models also successfully predict pathogen attachment for a second-generation library, and identify polymer surface chemistries that enhance or diminish pathogen attachment. A manuscript on work on multiple pathogen attachment models has been submitted.
Sparse feature selection methods have also identified a new mechanism for strontium biomaterial-induced differentiation of mesenchymal stem cells to bone. Strontium ranelate (Protelos) is a drug approved in the European Union for the treatment and prevention of osteoporosis. It reduces risk of vertebral and non-vertebral fractures in post-menopausal women. Although controversial, it is reported to have an anabolic and anti-catabolic effect on bone. Strontium ion's mechanism of action is not fully understood, but it is thought to up-regulate differentiation of osteoprogenitors or stimulate bone formation.53-55
David and his Imperial College co-workers,56 Molly Stevens, Eileen Gentleman, and Hélene Autefage, have evaluated the global response of human mesenchymal stem cells to strontium-substituted bioactive glasses using a combination of unsupervised biological and physical science techniques. Their objective analyses of whole gene-expression profiles, confirmed by standard molecular biology techniques, revealed that strontium-substituted bioactive glasses up-regulated the isoprenoid pathway, suggesting an influence on both sterol metabolite synthesis and protein prenylation processes.
In future, David hopes to see exploitation of new AI methods such as deep learning; improved descriptors for molecules that are effective and interpretable; exploitation of evolutionary methods of discovery aided by robotics; synergy of AI and evolutionary methods for adaptive evolution; adoption of in silico methods from drug discovery for materials and regeneration; development of autonomous or semiautonomous "closed loop" design methods; and more effective exploration of vast molecular or materials spaces.
Deep learning was predicted to be a breakthrough technology in 2013. Deep neural networks are not necessarily magic. According to the universal approximation theorem, a feed-forward network with a single hidden layer containing a finite number of neurons can approximate any continuous function, under mild assumptions on the activation function. This was first proved by Cybenko in 1989 for sigmoid activation functions. Hornik showed in 1991 that it is not the choice of the activation function, but the multilayer architecture itself which gives neural networks the potential of universal approximators.46
Deep learning methods have generated impressive improvements in image and voice recognition, and are now being applied to QSAR and QSAR modeling. A recent publication46 describes the differences in approach between deep and shallow neural networks, compares their abilities to predict the properties of test sets for 15 large drug datasets, discusses the results in terms of the universal approximation theorem for neural networks, and describes how deep neural networks may ameliorate or remove troublesome "activity cliffs" in QSAR datasets. Materials space is vast and at least in some of its many dimensions, the fitness landscape is smooth. This allows adaptation, one step (one mutation) at a time. Evolution and machine learning can be combined in adaptive learning (the Baldwin effect).
A recent review discusses the problems of large materials spaces, the types of evolutionary algorithms employed to identify or optimize materials, and how materials can be represented mathematically as genomes.57 It describes fitness landscapes and mutation operators commonly employed in materials evolution, and provides a comprehensive summary of published research on the use of evolutionary methods to generate new catalysts, phosphors, and a range of other materials. Another recent paper describes the materials genome in action.58
Machine learning methods have achieved wide applicability: for example, in aqueous solubility of drugs;59 polymers for stem cell growth;60 cubane as a benzene isostere;61 benign organic corrosion inhibitors;62 markers for stem cell division;63 materials for stem cell factories;64 adverse effects of nanomaterials;65 anticancer farnesyltransferase inhibitors;66 and prediction of materials properties.44
In summary, AI tools developed for therapeutic medicine also work well for regenerative medicine. Neural networks are machine learning methods that are very applicable to (bio)materials design. The universal approximation theorem means that deep learning methods should not be superior to shallow neural networks for molecular design. Bayesian regularized neural networks can generate robust, predictive models of many types of materials and properties. Sparse Bayesian feature selection methods can reduce the dimensionality of problems, improve interpretability, and generate robust models with better predictivity. Evolutionary methods, combined with machine learning (adaptive evolution) can find effective materials quickly and efficiently.
Erin Davis, chair of the ACS Division of Chemical Information, formally presented the Herman Skolnik Award to David Winkler at a reception held in honor of David, following the symposium.
Erin Davis and David Winkler


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"What is that feeling when you're driving away from people and they recede on the plain till you see their specks dispersing? – it's the too-huge world vaulting us, and it's good-bye. But we lean forward to the next crazy venture beneath the skies."
–Jack Kerouac
I love that bit of Kerouac (even though I don't particularly like him as a person). Our leaning forward toward the "next crazy venture" began just over a month ago.
Driving cross country felt like a long, tiring dream. Day after day spent under the sky, watching the land spread out in front of us. We passed windmills, sunflower fields, the tiniest towns and the biggest cities.Each night brought us to a new place, with people to learn from and sunsets to see.
I believe deeply that this country is best experienced from the ground. If we had more time, G & I would have rather taken back roads, but our 90West road trip still provided some beautiful insight into American life. Stop in small towns, eat on the ground, play the best music & stop to take photos; the journey is always worth it.

subset: commoncrawl


text: BIKE GRAPHIX JOINS FORCES WITH JUNIORMOTOX By JuniorMotoX Posted April 5, 2018 In News 0 0 BikeGraphix JOINS THE TEAM FOR JUNIORMOTOX 2018 April 4, 2018 BikeGraphix a leader in decals, plate backgrounds, custom graphics kits and much more has joined forces with JuniorMotoX for 2018. JuniorMotoX has become one of the premier events in motocross and it's unique indoor layout makes it an ideal match for a company like BikeGraphix to be involved with. Dan Hirner from BikeGraphix said " I heard about JuniorMotoX when it began and watched how quickly it grew. When the chance to get involved came up I knew we needed to jump onboard. The team at BikeGraphix really looks forward to being there and supporting all the top racing families in May." The team at JuniorMotoX is committed to putting on the best quality event possible which fits well with BikeGraphix approach to racing and business. Jay Reynolds who joined the JuniorMotoX team earlier this year said " I have worked with Dan and the guys at BikeGraphix for some time and they have a real connection to racing and work hard to support racing events around the country. It was a perfect fit with JuniorMotoX". JuniorMotoX will happen again this year on the weekend following the end of Supercross season, May 10-12, 2018. Be sure to register soon as classes are filling up quickly. Register HERE Visit BikeGraphix JuniorMotoX Recent Posts2018 RACE RESULTS2018 RACE RECAPJETT REYNOLD'S #79 AT JMXHAIDEN "DANGERBOY" DEEGAN TALKS JUNIOR MOTO X! Leave a Comment Cancel reply


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Merry Charms - Sunshine Smile Kidz
Regular price
* In-stocks - 16
* 2.5 x 2.5 cm (charm size)
* Crochet
* Nylon yard / acrylic
* Price for 1
* Every piece has unique blend of rainbow colour.
* Free featured plastic gift bag
* View free gifts with purchase here
Designed and crocheted by Lyann Yap.
A rainbow makes one smiles like hope shinning on them!
Happy crochet heart design with a super bright sunshine smile charm brightens life and lifts up life instantly.
It is a cheer-leader for any accessory such as bag zipper etc.
Every piece has a unique blend of rainbow colour and you'll get your special one!
You will get one set with featured gift bag at $1.00


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Abs, empathy and edge
Guru, Catherine Faulder, Published on 02/12/2016
» One hour with Chakrit Narula, a personal trainer at The Edge Boutique Gym (http://fb.com//theedgeboutiquegym) and you feel like you've done your bit for the year. Despite his military approach to working out, what we like about Chakrit is his ability to relate with us normal humans who don't work out - or plan to - 24/7. We aren't robots and we're very much driven by realness and that "yeah I'll get round to it" mentality. We stumble. We fall. We fail. Chakrit's seen about every colour of the human condition when it comes to physical fitness, and this translates in his ability to motivate us. He wasn't always all abs and bones you know. Here's his story.
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Kelly Salamack
B.A. Psychology, Siena College
Professional Experience
Kelly joined Perry in April 2018 with an extensive background in graphic design and a wide array of creative experience. Formally, Kelly was Senior Graphic Designer at The Grubb Company in the San Francisco Bay Area, a boutique residential real estate firm where she rebranded the 50-year-old company identity and created a brand standard for the organization, on top of many other marketing responsibilities.
Kelly was a member of the Division 1 Water Polo Team at Siena College and is a native of the San Francisco Bay Area.
Professional and Civic Affiliations
Kelly has certifications from the San Francisco General Assembly in HTML, CSS, Web Design, and User Experience Design.


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This page shows how to use Cilium for NetworkPolicy.
For background on Cilium, read the Introduction to Cilium.
You need to have a Kubernetes cluster, and the kubectl command-line tool must be configured to communicate with your cluster. If you do not already have a cluster, you can create one by using Minikube, or you can use one of these Kubernetes playgrounds:
To check the version, enter
kubectl version.
To get familiar with Cilium easily you can follow the Cilium Kubernetes Getting Started Guide to perform a basic DaemonSet installation of Cilium in minikube.
As Cilium requires a standalone etcd instance, for minikube you can deploy it by running:
kubectl create -n kube-system -f https://raw.githubusercontent.com/cilium/cilium/v1.3/examples/kubernetes/addons/etcd/standalone-etcd.yaml
After etcd is up and running you can deploy Cilium Kubernetes descriptor which is a simple "all-in-one" YAML file that includes DaemonSet configurations for Cilium, to connect to the etcd instance previously deployed as well as appropriate RBAC settings:
$ kubectl create -f https://raw.githubusercontent.com/cilium/cilium/v1.3/examples/kubernetes/1.12/cilium.yaml
configmap/cilium-config created
daemonset.apps/cilium created
clusterrolebinding.rbac.authorization.k8s.io/cilium created
clusterrole.rbac.authorization.k8s.io/cilium created
serviceaccount/cilium created
The remainder of the Getting Started Guide explains how to enforce both L3/L4 (i.e., IP address + port) security policies, as well as L7 (e.g., HTTP) security policies using an example application.
For detailed instructions around deploying Cilium for production, see: Cilium Kubernetes Installation Guide This documentation includes detailed requirements, instructions and example production DaemonSet files.
Deploying a cluster with Cilium adds Pods to the
kube-system namespace. To see
this list of Pods run:
kubectl get pods --namespace=kube-system
You'll see a list of Pods similar to this:
cilium-6rxbd 1/1 Running 0 1m
There are two main components to be aware of:
cilium Pod runs on each node in your cluster and enforces network policy
on the traffic to/from Pods on that node using Linux BPF.
Once your cluster is running, you can follow the Declare Network Policy to try out Kubernetes NetworkPolicy with Cilium. Have fun, and if you have questions, contact us using the Cilium Slack Channel.
Was this page helpful?
Thanks for the feedback. If you have a specific, answerable question about how to use Kubernetes, ask it on Stack Overflow. Open an issue in the GitHub repo if you want to report a problem or suggest an improvement.


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When you imagine a Pilates aficionado, you probably think of a young, thin, healthy and physically active human. I am none of those things.
Please Allow me to change that preconceived and incorrect notion.
Pilates, also known as Controlology, was actually designed to be rehabilitative.
I'm 50 years. I am obese. I exist with an autoimmune disease called myasthenia gravis, which causes severe muscle weakness. I have had this disease since I was 14 years old.
As you can see I am not your typical Pilates aficionado. I was introduced to Pilates by my physical therapist, Emelia Brogna. She felt Pilates was a perfect fit for me because of the reformer helps you complete movements which is a real issue for me because I have a hard time completing the movement because my muscles get so weak and fatigued. I had no cell memory of certain movements because my body has had this condition for so long.
As my physical therapy sessions were coming to an end, Emelia suggested I meet Arica Bronz, who is one of the amazing Pilates instructors at All Wellness.
Together, Amelia and Erica designed a program for me to start with very simple stretching and range of motion movements. In discovering how my muscles worked, we were able to design a program that would help improve my core strength and my balance. Emphasis on balance because I have been known to fall and I am not able to get up without help.
In 2015 I started a clinical trial drug that helped increase my muscle strength. We all knew it was a temporary fix. we seized the opportunity to try to make the most of this new strength and build up as much strength and muscle as possible while we had the chance.
Use of the reformer, the Trap table, some stretching with bands and sitting on a Yoga ball has increased my flexibility, strength and endurance in ways you cannot imagine.
I am a person that couldn't even sit up from a laying position. I can now do a modified Pilates program. There are things I can do that were unimaginable for me two and a half years ago. My posture is much improved. My breathing is easier. I have better range of motion. The flexibility I have gained is immeasurable.
What I am trying to say in this rambling statement is simply this, Pilates is for all abilities, all sizes, all ages. Programs can be modified for your physical needs, if need be.
Think outside the box and you may just discover your body can do things that were once unimaginable.
~ Roseanne Lathbury, All Wellness Client and Lover of Pilates


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Writing for Pete's blog allows me the opportunity to speak to a nationwide and perhaps international audience. While it's not uncommon for me to have a choir to preach to, I feel I have to up my game a little and speak not about local taxes issues or individual corrupt politicians or odious ordinances, but I have to speak to things that are of national merit. One thing I have learned and can share with you is that the virtue of courage is required for all effective political action.
Courage is a requirement for leadership, if you cannot stand up and motivate yourself to do what needs to be done even in the face of the slings and arrows of outrageous fortune, frankly it won't get done. People respond to courage and courage is contagious. When they see you being courageous they instinctively want to be on the side of that person, they want to be courageous too. So courage is the most important of all political of all virtues in politics.
With courage being so important we must figure out how to grow our own courage and how to transmit it to other people, we must expand it in every possible way. It seems to me that courage is like a muscle the more you use it the more of it you gain. It also seems that courage is the opposite of bullying; if you develop a habit of bullying people you lose your courage. Using social media to confront politicians and policy makers with truths they would like to ignore grows your courage. Posting ad hominem attacks on anonymous trolls decreases your courage.
It is not enough to be courageous by yourself you must enlist others friends Neighbors in your courageous action because courage is action. Sometimes it's easier to be courageous in a group often the opposite is true groups make cowards of us. The important thing is to surround yourself with courageous people. I gain most of my courage from the patriotic members of the Worcester Tea Party.
Here's a little exercise you can try, are you courageous enough to listen to someone you disagree with and not lose your patience with them? Are you courageous enough to go to a meeting supporting a proposition you oppose stand up and speak out against it in a room full of people that you know will despise you for that? These are things that take real courage and these are the things that need doing today more than ever.
Matt O'Brien
President: Worcester Tea Party
On FaceBook
The WTP is enjoying the privilege of posting here weekly because Pete has a lot of courage and is a Hero of our Republic.
Please Support the courageous work of the Worcester Tea Party.


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It's coming up for Valentine's Day! And one (very sexy and deeply romantic) way of connecting with your beloved is to go to a spa as a couple. You can spend time in beautiful surroundings being pampered and indulged. Enjoy a sensual massage with delicious smelling aromatherapy oils (for example) and then think how relaxed and how beautiful you will feel. And how you might reap the benefits when you get home…
Some things you should know before you start though:
The first thing you need to do is check that the spa actually offers couple's treatments. Essentially a couple's treatment is the same as any other one, but the room will have two massage beds side-by-side, and you will be massaged at the same time, for example. If you are having a couple's pedicure, you will each have your own pedicurist, but you will be sitting in chairs, side-by-side. But not all spas have the facilities to provide the space for couple's treatments so do check.
On the other hand, you may prefer to do your own thing when it comes to treatments (I remember my own beloved being traumatised when he had to wear tiny little paper broeks when we had a couple's body scrub. Although, come to think of it, perhaps the LADY who was doing his treatment was more traumatised by his tiny paper broeks, if you get my drift). This way, you can each do what interests you (and avoid being traumatised or bored). You can meet up in the steam room or Rasul chamber, for instance, for some bonding time.
Book in advance if you possibly can. That way you can get the time and day that you want and the treatments you would prefer (and the great, money-saving packages that many spas offer).
There are some great deals out there; you just need to spend a bit of time with our friend Google. But to save you the effort, here are a few that might be what you're after:
• Wedgeview Country House and Spa in Stellenbosch is a recipient of a Trip Advisor's Certificate of Excellence 2012, and is offering a great couple's package which includes a night's stay with breakfast as well as several treatments for R1595 per person sharing. Contact them on 021 881 3525.
• Librisa Spa at the Mount Nellie is offering a one-hour Bliss for Two package, followed by afternoon tea in the hotel lounge, for R1550. 021 483 1000.
• The Soulstice Day Spa in Pretoria is offering an Earth and Moon package for the two of you – where all the treatments take place in your own Luxury Executive Couple's suite, so you can get plenty of alone time! You will also have your own hydro bath, sparkling wine and a lunch platter. R3500 for five hours. 012 809 0444.
If paying for spa treatments is not in your financial plan or you know there is no way your man will get on board with the spa idea (see aforementioned paper broeks anecdote), why not try some romantic spa treatments in the comfort of your own home?
You could try:
• A warm bath together. Warm water relaxes muscle tension and if you add some bath oil, you can enjoy not only the wonderful smell (always great for the soul) but that slippery, sensual feeling as you touch each other. You might want to add a couple of glasses of sparkling wine to the mix…
• Once you're done, wrap each other in warm, toasty, enormous towels (which you have cleverly prepared in advance by throwing into the dryer and then rolling tightly into one large towel to keep the heat in).
• Now, smooth each other with moisturiser (make sure the scent isn't too girly, though). Or you might want to go with massage oils.
• Light a few candles and add a sizzling back rub and you're set for the rest of the evening! You're welcome!
Image: wavebreakmedia/Shutterstock.com
Other articles you make be interested in:
Fabulous face masks
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Bargain beauty buys for women
Bargain beauty tips
Romance on a budget


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Lavender Face & Body Lotion
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Lavender Face & Body Natural Lotion.
Formulated with an organic base to replenish and soothe dry skin. Key ingredients include Organic Aloe Juice, Organic Lavender Hydrosol, Rose Water and Organic Coconut Oil. This creamy lavender lotion is gentle enough for all skin types.
Lavender is known for it's calming relaxing properties that can help you sleep.
To Use: Before Bed, Rub over dry clean skin and blend in.
Best applied to upper body to sense the smell. Arms, Wrists, Chest, Neck.
Paraben Free blend! Created with a base that has 83% organic ingredients.


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—Sam Adler-Bell focuses on labor and mass incarceration.
Follow @samadlerbell
"Response to Vivek Chibber," by Bruce Robbins. n+1, January 9, 2014.
This piece by Columbia English professor Bruce Robbins represents the latest volley in a months-old academic dust-up inaugurated by the publication of Vivek Chibber's Postcolonial Theory and the Specter of Capital (Verso 2013) in March. Thanks to the miraculous hype machine at Verso Press—the hip wizards of leftist publishing, imbuing new books about Marxism with the cultural relevance of a Radiohead album—the fashionably unfashionable quality of Chibber's central argument (that universal history in a Marxist mode is not only possible but necessary), and the pugnaciousness of Chibber's attack on venerated Subaltern Studies historians like Partha Chatterjee and Ranajit Guha, the book has become something of a lightning rod. And it's been fun to follow the little squirmishes: Axel Andersson's piece in the Los Angeles Review of Books, Robbins's review in n+1, Chibber's response to Robbins in Jacobin, Robbins's response to Chibber (above), not to mention a moderated debate between Chibber and Chatterjee at NYC's Historical Materialism conference—which Verso live-tweeted as if it were a WWE prizefight ("Y'all ready for the Chibber/Chatterjee cage match that's about to start? #postcolonialism").
—Dustin Christensen focuses on Latin American politics and sports.
Follow @dustyc123
"Mexico States Leave Millions on the Table, Thwart Police Reform," by Patrick Corcoran. InSightCrime, January 14, 2014
The Mexican government has recently deployed troops and federal police to the southwestern state of Michoacán in an attempt to disarm vigilante "self-defense" groups. These groups have sprung up in the area during the last year to combat both corrupt local police forces and the Knights Templar drug cartel. Patrick Corcoran has an excellent piece about local governments' failure to spend some $190 million in federal funds available last year for vetting local police forces. Using this money would be a huge first step towards improving local policing capacity, filling the institutional gap that makes armed vigilante groups necessary in the first place.
—Laura Cremer focuses on labor, gender and the historicization of culture and politics.
Follow @lfcremer
"In the Name of Love," by Miya Tokumitsu. Jacobin, Issue 13.
Miya Tokumitsu writes about the rise of a new, Steve Jobs–approved mandate for modern workers: "Do what you love; love what you do." She discusses the dire social and political consequences of accepting the idea that the road to happiness lies in "fun" work rather than less work and better compensation. The essay only begins to explore certain aspects of the problem, including the ways it can cut across class lines, but it does remind us that it's not only "elites" who are harmed by the kind of thinking it represents (which helps normalize unpaid internships and the replacement of full-time professors with low-paid adjuncts): the idea that "doing what you love" is a personal choice also erases the experiences of everyone who can't afford to do so. The essay should remind us that we can't afford to accept social mobility as a substitute for greater equality or rely on individual solutions to collective problems.
—Cecilia D'Anastasio focuses on ethics, feminism, press freedom and tech.
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"Did God Make These Babies Moral?," by Paul Bloom. The New Republic, January 13, 2014.
In his accessible and well-reasoned investigation into altruism, Yale Professor of Cognitive Science Paul Bloom asks, "Why would someone risk his life for a stranger?" Bloom's piece opens with the story of an ordinary man who dove onto subway tracks—with a train approaching—to save the life of somebody he'd never met. Bloom uses the emergence of altruism in the human species as a reference point for a larger inquiry into evolution versus intelligent design. Is selfless morality a product of natural selection or of the supernatural? In asking where our higher moral faculties come from, Bloom takes us through an intellectual history of how scientists and thinkers dealt with the question of functional morality.
—Simon Davis-Cohen focuses on self-governance, climate adaptation and institutional voids.
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"Court Of Appeals, Division III of the State of Washington: Appellant's Opening Brief. January 6, 2014.
The City of Spokane and local civic groups are appealing their county's decision to remove a citizen initiative from last November's ballot. The initiative would elevate neighborhood associations' decision-making power, workers' constitutional rights and rights of the Spokane River above corporate constitutional rights within the municipality. A separate initiative removed from the ballot, though not included in the appeal, would introduce a voter bill of rights and elevate said rights above corporate constitutional rights, locally. Prompting the question: What should US citizens be allowed to vote on?
—Justine Drennan focuses on human rights and minority groups in Asia.
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"China's Crackdown on Cyber Activism," by Michael Caster. The Diplomat, January 13, 2014.
Caster looks at the ethical tensions behind a burgeoning form of Chinese online activism called the "human flesh search," in which netizens make "an independent investigation into the personal details of suspected wrongdoers"—largely government officials suspected of corruption—and share information and images about them online. These operations can spread false rumors and "have been equated with both cyber activism and cyber vigilantism." But Caster believes in their potential, criticizing the Chinese government's recent threats to stifle them, and suggesting that, given individual campaigns' success so far in prompting court actions against corrupt officials, they're an important part of the Internet's potential for "slowly forcing Chinese society to be more participatory and transparent."
—Corinne Grinapol focuses on education and international relations/national security.
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"NSA phone record collection does little to prevent terrorist attacks, group says," by Ellen Nakashima. The Washington Post, January 12, 2014.
What often gets lost in the debate between preserving freedom vs. protecting Americans from attack is the efficacy of methods used to identify and thwart terrorist plots. As Ellen Nakashima describes in the findings of a New America Foundation analysis of the specific investigative methods used in 225 cases, the NSA's "bulk collection of phone records" had an insignificant impact. What's more, the NSA doesn't effectively sort through or share the data with other agencies. America's counterterrorism complex suffers from a too-much-data problem, rather than a not-enough-data problem, and this article is a good step toward dismantling the misconception that trampling civil liberties is a necessary and effective way to fight terrorism.
—Mara Kardas-Nelson focuses on health.
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"Obesity Rates Are Falling Among The Affluent And Well-Educated, But Rising Among The Poor," by Sy Mukherjee. ThinkProgress, January 14, 2014.
The article outlines the results of a recent Harvard report that finds adolescent obesity rates are falling among the wealthy while rising among the poor. There are several suggestions as to why: even though poor children consume fewer calories, they're also less likely to exercise and more likely to rely on unhealthy food. They also may experience more stress than their wealthy counterparts. The article is important because it deals with one of the biggest health problems the United States is facing today, and demonstrates how inequality impacts our health and behavior.
—David Kortava focuses on sustainable development.
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"How the War on Poverty Succeeded (in Four Charts)," by John Cassidy. The New Yorker, January 14, 2014.
Last week Paul Ryan announced that the War on Poverty "has failed." Here John Cassidy repudiates this unexamined truism of the right and discusses a new Columbia University study suggesting that poverty has declined dramatically since the mid-1960s, when the Johnson administration launched the good war and introduced the now famous phrase into public discourse. Using new, more comprehensive metrics in lieu of the crude "official poverty measure," the researchers found that poverty has actually fallen, by some 40 percent since the mid-1960s. Moreover—and contrary to Ryan's contention that we "keep dumping money into programs we know don't work"—the researchers conclude that the drop is best explained by the emergence of government programs like Social Security, Medicare, food stamps, housing subsidies and tax credits for the low-paid.
—Benjamin Pokross focuses on education and the arts.
"When Minority Students Attend Elite Private Schools," by Judith Ohikuare. The Atlantic, December 17, 2013.
Judith Ohikuare brings her personal experiences to bear in a discussion of the recent documentary American Promise, which tells the story of two African-American students attending elite New York City prep schools. Ohikuare puts the film in a larger context and shows what it really takes for institutions to have a commitment to diversity.


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Join Us For Kohl's x Studio Tone It Up LIVE Workout!
Hey gorgeous!! Come work out with us ;) We're leading a total body toning sesh in Santa Monica today with our partner KOHL'S and we're sharing the whole thing on Facebook Live and right here! Get ready for some serious sculpting and maybe a lil' dance party too 💪💃


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CPL-33 National Vice President for Women and Fair Practices
Tyrone L. Covington is a native of Brooklyn, New York. He garnered the passion to begin helping people at the tender age of 16. In 2001, Tyrone was hired as a Federal Correctional Officer at the Metropolitan Correctional Center, New York, where he held positions of increasing responsibility in L-3148 as Shop Steward. In 2007, he was elected as President of L-3148. In 2014, Tyrone was selected unanimously in the Northeast region as Regional Fair Practices Coordinator, where he served the Council respectively until elected as National Vice-President for Women and Fair Practices.
In his tenure, Tyrone built an impeccable work record in relatively a short span of time. He racked up impressive wins in EEO, MSPB, Arbitration and before the Federal Labor Relations Authority (FLRA). He has won millions in back compensation for the local membership. Tyrone is the recipient of multiple Council awards, including the coveted Distinguished Leadership Award, W.H McKee National Presidential Award. As NVP, he has direct and total oversight of the EEO program within the Bureau of Prisons.
Tyrone Covington
National Vice President for Women and Fair Practices
Cell: 347-723-4348


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Despite snow and cold temperatures, approximately 200 American Baptist women from all around New Jersey journeyed to Fountain Baptist Church in Summit to attend this year's ABWM Love Gift Luncheon. In 2011, American Baptist Women in New Jersey raised over $12,000 for American Baptist missions through Love Gift. Here is a video report of the highlights of the event:
Dr. Lee B. Spitzer brought greetings from the region at the luncheon. Here are his remarks:


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The men's G3 parka from Matchless has a waxed cotton shell with chunky zip and button closure, extra-large pockets to the front and button straps to the cuffs. The hooded jacket features signature tartan lining and a brand badge to the left sleeve.
Please contact us for our Delivery & Returns Policy


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Protein is an essential nutrient needed to build muscle, repair and maintain connective tissue, and synthesize enzymes. Most Americans are not protein deficient, although extreme poverty, old age and vegetarianism are significant risk factors. In contrast, many bodybuilders and serious athletes not only eat protein-rich foods, but they also supplement with protein bars and powders to maximize the "building blocks" or amino acids available to their bodies for muscle building. However, consuming too much protein on a daily basis for many weeks or months is damaging to the body, especially the kidneys and possibly the liver. Blood liver tests are an accurate way of measuring liver function.
Liver Blood Tests
Your liver is primarily a filtering and detoxification organ, although it's also important for storing glycogen and producing cholesterol and protein-based compounds such as albumin and a variety of enzymes. A series of blood tests are used to assess liver function. Some compounds, such as albumin, are decreased with liver damage, whereas bilirubin levels and many enzymes become elevated within the blood. High levels of bilirubin, commonly known as jaundice, lead to yellowing of the eyes and skin, which is a classic indication of liver damage and dysfunction. Enzymes that are most commonly measured in liver function assessments are best known by their abbreviations and include ALT, AST, ALP, GGT and LDH. These enzymes are present in liver cells and leak into the blood with liver damage.
Factors That Affect Liver Tests
Many factors, diseases and conditions can increase liver enzymes and affect liver blood tests. For example, AST is also found in heart and skeletal muscle, so raised blood levels are also seen with heart attacks and skeletal muscle damage from strenuous exercise. As such, elevated liver enzymes don't always indicate serious liver damage. ALT enzyme is more liver specific because it's only found in liver cells, so its elevated value is more indicative of liver damage. However, other factors are more damaging to the liver than high protein consumption, including alcoholism, pharmaceutical use and liver infection or hepatitis, according to "Harrison's Principles of Internal Medicine." High protein consumption is much more likely to cause kidney damage and dysfunction long before any serious liver issues.
Protein Requirements
The recommended amount of daily protein needed to maintain normal bodily functions ranges from about 40 to 70 grams, depending on your gender, age and body composition and weight. However, if you exercise and lift weights to build muscle, your requirements are higher. Modern research indicates that athletes should consume between 0.5 and 0.8 grams of protein per pound of body weight on days they workout, which equates to between 90 and 160 grams for most male bodybuilders. Amino acids must be processed by your liver, which can be taxing in large amounts, but your kidneys take more of a beating by having to filter out the byproducts and excesses.
Protein Supplements
Common protein supplements include whey, casein, egg albumin, soybeans and wheat proteins. They are sold as powders or mixed into a variety of protein and energy bars. Whey and casein are both found in milk and are complete proteins, as are supplements derived from egg and soybeans. Wheat-based protein supplements are incomplete, which means they are missing at least one essential amino acid. Overall, protein supplementation in moderation does not damage the liver, although the act of lifting heavy weights can raise certain liver enzymes in your blood. In high doses over many weeks or months, protein is damaging to your kidneys and acidic for your blood, which would likely lead to noticeable symptoms before any liver damage occurs. Consult your doctor about the symptoms of liver dysfunction and the most common causes.


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Back to Cat Artwork Index
Do you have a favourite piece of original Cat Artwork? Show it off to the World Wide Web here at Moggies. Send any artwork as a JPG electronic picture attached to an e-mail to
with a brief description and details about the artist.
Artist: Gavin Mundy
Canvas Creatures
About the Artist:
My name is Gavin Mundy. Apart from pets, and animals in general, I do landscapes and other genres.
I do exhibit and have been involved in local, national and international shows, venues ranging from a few miles from me to Manchester Science Museum, Paris and even at NASA in the USA.
Canvas Creatures. Here you can order your pet portraits (whatever species they may be). I work from photos that you supply.
Each portrait begins with a discussion of what you are looking for in the painting. You may have a specific idea already or you might not have any idea of what you'd like. Either way I'll do some sketches and we can discuss ideas for the portrait.
Portraits usually have a plain or simple background as this tends to set off the subject better. Overtly detailed backgrounds or settings are possible but will be charged extra. Progress can be viewed via this website.
I'll ask for several good photos of your pet to work from. If the photos do not resemble your pet neither will the painting! Any supplied photographs will be returned to you with the finished painting.
I can also receive digital photos by
A beautiful example of Gavins work is below:
Cat Portrait in Acrylic on Canvas board.
Back to Cat Artwork Index


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How to Practice Effectively
One of the most important skills necessary for effective practicing is self-awareness. Without it, you lose the ability to monitor your level of focus during a practice session and run the risk of mindlessly going through the motions of what could have been a productive use of time.
Just like with meditation, when your attention drifts from the task at hand, it is imperative you realize your mind has wandered so you can then bring back into focus that which you set out to practice. It's worth mentioning that meditating will, in fact, aid in your ability to maintain a high level of concentration while practicing music.
Not sure how to meditate? Here's your six-sentence tutorial:
Sit upright in a quiet place and focus all of your attention on your breathing.
Now, because the experience of air moving in and out of your lungs isn't the most exciting thing in the world, there's a good chance your mind will wander and end up thinking about where to get lunch.
Don't fret.
The moment you realize your attention has strayed, simply refocus your awareness on your breath.
That's all there is to it.
Rinse and repeat for 10 minutes or more.
When you practice music after meditating, you may find yourself thinking about something completely unrelated to the exercise you're supposed to be perfecting. Again, don't despair. Be grateful you caught yourself drifting, and settle back into the present moment so you can resume practicing at full mental capacity.
Give it a try and comment below with any success stories, questions, or random thoughts that popped into your head while meditating and practicing.