Search

The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel pain target due to its striking human genetics. However, clinically available drugs (e.g. lidocaine, carbamazepine, etc.) are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9, and the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. Moreover, understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidateGDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor series. To advance inhibitor design targeting the NaV1.7 channel, we established an iterative system to routinely obtain high-resolution ligand-bound NaV1.7 structures using cryogenic electron microscopy (cryo-EM). We report thatGDC-0310engages the NaV1.7 voltage-sensing domain 4 (VSD4) through an unexpected binding mode orthogonal to the arylsulfonamide class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, this study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. It also underscores an important role of the membrane bilayer in the discovery of selective NaV channel modulators.

Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.

Significance The uptake of molecules into cells, known as endocytosis, requires membrane invagination and the formation of vesicles. A version of endocytosis that is independent of actin polymerization is aided by the assembly of membraneless biomolecular condensates at the site of membrane invagination. Here, we show that endocytic condensates are viscoelastic bodies that concentrate key proteins with prion-like domains to enable membrane remodeling. A distinct molecular grammar, namely the preference for glutamine versus asparagine residues, underlies the cohesive interactions that give rise to endocytic condensates. We incorporate material properties inferred using active rheology into a mechanical model to explain how cohesive interactions within condensates and interfacial tensions among condensates, membranes, and the cytosol can drive membrane invagination to initiate endocyosis., Membrane invagination and vesicle formation are key steps in endocytosis and cellular trafficking. Here, we show that endocytic coat proteins with prion-like domains (PLDs) form hemispherical puncta in the budding yeast, Saccharomyces cerevisiae. These puncta have the hallmarks of biomolecular condensates and organize proteins at the membrane for actin-dependent endocytosis. They also enable membrane remodeling to drive actin-independent endocytosis. The puncta, which we refer to as endocytic condensates, form and dissolve reversibly in response to changes in temperature and solution conditions. We find that endocytic condensates are organized around dynamic protein–protein interaction networks, which involve interactions among PLDs with high glutamine contents. The endocytic coat protein Sla1 is at the hub of the protein–protein interaction network. Using active rheology, we inferred the material properties of endocytic condensates. These experiments show that endocytic condensates are akin to viscoelastic materials. We use these characterizations to estimate the interfacial tension between endocytic condensates and their surroundings. We then adapt the physics of contact mechanics, specifically modifications of Hertz theory, to develop a quantitative framework for describing how interfacial tensions among condensates, the membrane, and the cytosol can deform the plasma membrane to enable actin-independent endocytosis.

Um die finanzielle Tragfähigkeit der Umsetzung eines verbesserten Kleinwasserkraftanlagendesigns hinsichtlich des chinesischen Elektrizitätsmarkts abzuschätzen zu können, wurde ein einfach umzusetzender Bewertungsansatz erstellt. Grundlage für diesen Ansatz war die Durchführung einer entsprechenden Bewertung für das Kleinwasserkraftwerk Shichang im Flussgebiet Chong'an in der Provinz Guizhou. Aus der beispielhaften Bewertung wurden Empfehlungen abgeleitet, die eine Fokussierung auf die relevanten Parameter erlauben und die anzustrebenden Bereiche der finanziellen Leistungsindikatoren aufzeigen.

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24 showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.

Na

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Na

Over a century ago, colloidal phase separation of matter into non-membranous bodies was recognized as a fundamental organizing principal of cell "protoplasm." Recent insights into the molecular properties of such phase-separated bodies present challenges to our understanding of cellular protein interaction networks, as well as opportunities for interpreting and understanding of native and pathological genetic and molecular interactions. Here, we briefly review examples of and discuss physical principles of phase-separated cellular bodies and then reflect on how knowledge of these principles may direct future research on their functions.

The spontaneous nature of biopolymer phase separation in cells entails that the resulting condensates can be thermodynamic machines, which, in the process of condensing, can take on distinct forms themselves and deform neighboring cellular structures. We introduce here general notions of material and mechanical properties of protein condensates with an emphasis on how molecular arrangements and intermolecular interaction within condensates determine their ability to do work on their surroundings. We further propose functional implications of these concepts to cellular and subcellular morphology and biogenesis.

Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-π interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.

Clathrin-mediated endocytosis (CME) underlies intra- and extracellular material trafficking in eukaryotes, and is essential to protein metabolism, intercellular signaling, membrane remodeling and other cell regulatory processes. Although CME is usually driven by F-actin polymerization, membrane invagination can also occur through actin independent mechanisms. Here, we show that viscoelastic protein condensates that form via liquid-liquid phase separation at the sites of endocytosis initiation facilitate actin independent CME. Binding energies of the condensate with the membrane and surrounding cytosol provides work required to drive membrane invagination. Our findings expand the repertoire of functions associated with protein condensates that form via liquid-liquid phase separation to include their ability to do work at soft interfaces, thus shaping and organizing cellular matter.

SummaryIf specific and functional kinase- or phosphatase-substrate interactions are optimized for binding compared to promiscuous interactions, then changes in phosphorylation should occur faster on functional versus promiscuous substrates. To test this hypothesis, we designed a high temporal resolution global phosphoproteomics protocol to study the high-osmolarity glycerol (HOG) response in the budding yeast Saccharomyces cerevisiae. The method provides accurate, stimulus-specific measurement of phosphoproteome changes, quantitative analysis of phosphodynamics at sub-minute temporal resolution, and detection of more phosphosites. Rates of evolution of dynamic phosphosites were comparable to those of known functional phosphosites and significantly lower than static or longer-time-frame dynamic phosphosites. Kinetic profile analyses indicated that putatively functional kinase- or phosphatase-substrate interactions occur more rapidly, within 60 s, than promiscuous interactions. Finally, we report many changes in phosphorylation of proteins implicated in cytoskeletal and mitotic spindle dynamics that may underlie regulation of cell cycle and morphogenesis.

SummaryMembrane invagination and vesicle formation are key steps in endocytosis and cellular trafficking. Here, we show that endocytic coat proteins with prion-like domains (PLDs) form hemispherical puncta in the budding yeast, S. cerevisiae. These puncta have the hallmarks of biomolecular condensates and enable membrane remodeling to drive actin-independent endocytosis. The puncta, which we refer to as endocytic condensates, form and dissolve reversibly in response to changes in temperature and solution conditions. The condensates are organized around dynamic protein-protein interaction networks, which involve interactions among PLDs with high glutamine contents. The endocytic coat protein Sla1 is at the hub of the protein-protein interaction network. Using active rheology, we indirectly characterized the material properties of endocytic condensates. These experiments show that endocytic condensates are viscoelastic materials and allow us to estimate the interfacial tension between endocytic condensates and their surroundings. We then adapt the physics of contact mechanics, specifically the contact theory of Hertz, to develop a quantitative framework for describing how interfacial tensions among condensates, the membrane, and the cytosol can deform the plasma membrane to enable actin independent endocytosis.

A practical synthesis of a potent, selective, and orally efficacious diacylglycerol acyltransferase-1 (DGAT-1) inhibitor, is described. This synthesis is suitable for multi-kilogram scale with high regioselectivity and stereoselectivity. The synthesis involves a Knoevenagel condensation with Meldrum’s acid followed by the stereoselective addition of phenyl cuprate, regioselective Friedel–Crafts acylation, cyclization, and a regioselective reduction through an enol triflate with catalytic platinum oxide to provide the desired compound in 5.2% yield over 12 steps.

The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown impressive clinical efficacy in a range of B-cell malignancies. However, acquired resistance has emerged, and second generation therapies are now being sought. Ibrutinib is a covalent, irreversible inhibitor that modifies Cys481 in the ATP binding site of Btk and renders the enzyme inactive, thereby blocking B-cell receptor signal transduction. Not surprisingly, Cys481 is the most commonly mutated Btk residue in cases of acquired resistance to ibrutinib. Mutations at other sites, including Thr474, a gatekeeper residue, have also been detected. Herein, we describe noncovalent Btk inhibitors that differ from covalent inhibitors like ibrutinib in that they do not interact with Cys481, they potently inhibit the ibrutinib-resistant Btk C481S mutant in vitro and in cells, and they are exquisitely selective for Btk. Noncovalent inhibitors such as GNE-431 also show excellent potency against the C481R, T474I, and T474M mutants. X-ray crystallographic analysis of Btk provides insight into the unique mode of binding of these inhibitors that explains their high selectivity for Btk and their retained activity against mutant forms of Btk. This class of noncovalent Btk inhibitors may provide a treatment option to patients, especially those who have acquired resistance to ibrutinib by mutation of Cys481 or Thr474.

Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i)10 nM for the mTOR kinase and500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.

A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i)1.0 nM and were highly (100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.

RÉSUMÉ Introduction : Le Lower Extremity Functional Scale a été traduit en français en 2006. La version canadienne-française se nomme l'Échelle fonctionnelle des membres inférieurs (ÉFMI). La validité de construit et la fiabilité test-retest de l'ÉFMI n'ont pas encore été examinées. But : Examiner la fiabilité test-retest, la consistance interne et la validité de construit de l'ÉFMI. Méthodologie : Trente-quatre participants ayant subi une chirurgie ou une blessure à un membre inférieur ont rempli un questionnaire démographique et complété l'ÉFMI lors d'une évaluation initiale alors qu'ils étaient hospitalisés. Ils ont à nouveau complété l'ÉFMI dans un intervalle de 72 heures après la première évaluation. Le coefficient de corrélation intra-classe (CCI) et le coefficient kappa ont été utilisés afin d'examiner la fiabilité de type test-retest de l'ÉFMI. Le coefficient alpha Cronbach a été calculé pour évaluer la consistance interne. L'analyse factorielle a été utilisée pour examiner la validité de construit afin de déterminer le nombre de dimensions et leur signification respective. Résultats : Le CCI s'élève à une valeur de 0,92 [0,88–0,96] (IC: 95%). Le résultat du test α-Cronbach est de 0,95 (0,91–0,99) IC à 95%. L'analyse factorielle révèle que tous les éléments de l'ÉFMI se logent sur une dimension principale. Conclusion : Les résultats montrent que la version canadienne-française de l'ÉFMI est un outil unidimensionnel qui offre une fiabilité test-retest et une consistance interne excellentes.

RÉSUMÉ Introduction : Le Rehabilitation Network of Ottawa-Carleton (RENOC) recommande à ses établissements de santé d'utiliser le Lower Extremity Functional Scale (LEFS). Puisque le RENOC dessert une clientèle anglophone et francophone, il s'imposait de traduire le LEFS pour l'évaluation de la clientèle francophone. But : Produire une traduction canadienne-française du LEFS sous l'appellation proposée « Échelle fonctionnelle des membres inférieurs (ÉFMI) » et examiner la validité de son contenu. Méthodologie : Nous avons utilisé une approche modifiée de la méthodologie de validation transculturelle de questionnaires de Vallerand (1989). Une traduction renversée parallèle du LEFS a d'abord été complétée. Ensuite, un comité d'experts a examiné les deux versions préliminaires et a créé la première version expérimentale de l'ÉFMI. Cette version fut évaluée par un deuxième comité d'experts, dont les commentaires menèrent à une deuxième version expérimentale. Finalement, 35 professionnels de la réadaptation évaluèrent la version expérimentale de l'ÉFMI sur une échelle d'ambiguïté et proposèrent les modifications finales. Résultats : Pour les différents énoncés de la version finale de l'ÉFMI, les moyennes sur l'échelle d'ambiguïté démontrent un niveau d'ambiguïté relativement faible puisqu'elles varient entre 1 et 2.54. Conclusion : Les quatre étapes rigoureuses du processus ont permis de produire une version valide du LEFS en français.

A Nicotiana benthamiana transient expression system was used to express single antigen and dimeric combinations of the human rotavirus (HRV) VP7 and a truncated VP4 (VP4Δ) proteins fused with Salmonella typhimurium's flagellin fljB subunit. Immunoblot analyses using rabbit antibodies generated against these proteins demonstrated that the constructs were successfully expressed with yields ranging from 0.85 to 31.97 μg of recombinant protein per gram of fresh leaf tissue. Expressing the single and dimeric antigens has no effect on plant growth and development except for VP7 and VP4Δ::VP7, which show mild necrotic lesions. Immunization of mice with proteins from leaves transformed with constructs bearing the fljB moiety elicited an fljB-specific humoral response. The Nicotiana benthamiana transient system is efficient to express multiple combinations of pathogen proteins and demonstrates the potential of generating a Salmonella typhimurium subunit vaccine in plants.

Using Sorafenib as a starting point, a series of potent and selective inhibitors of CDK8 was developed. When cocrystallized with CDK8 and cyclin C, these compounds exhibit a Type-II (DMG-out) binding mode.

Contrepartie du monopole de représentation syndicale, le devoir de juste représentation s’impose aux syndicats du Québec en vertu du Code du travail depuis 1978. Parallèlement, à la faveur de la promulgation des lois et des chartes des droits de la personne au Québec depuis les années 70, la promotion des droits de la personne fait craindre à certains observateurs les effets interactifs de deux ensembles juridiques très différents (droits de la personne et droit des rapports collectifs de travail) et, entre autres, l’effet perturbateur d’une logique dite d’intérêts individuels. Les auteurs étudient ici empiriquement l’évolution du recours pour manquement au devoir de juste représentation en faisant une revue de toutes les décisions rendues en vertu de l’article 47.3 du Code du travail. S’ils ne peuvent constater que les recours fondés sur une condition protégée par les lois sur les droits de la personne augmentent, en revanche, la jurisprudence en matière de devoir de juste représentation amène les auteurs à s’interroger quant à la faible protection de la norme d’égalité dans le champ du droit au travail que permet l’application de l’article 47.3. L’arrêt Parry Sound rendu en 2003 pourrait cependant changer la donne., As a counter-balance to trade unions’ representative monopoly, Québec unions have since 1978 been held answerable to the duty of even-handed representation. Likewise, owing to the enactment of Québec human rights statutes and charters since the 1970s, the promotion of human rights has led some observers to fear the interactive effects of two very different fields of legal intervention (human rights and group relationships based upon Labour Law), and also, the disruptive effects of logical reasonings centred on individual interests. As such, the authors empirically delve into the evolution of recourses for neglect of one’s duty for providing even-handed representation by reviewing all the rulings handed down under subsection 47.3 of the Labour Code. While they fall short of observing that recourses based upon a condition protected by human rights legislation are increasing, they nonetheless note that precedents regarding the duty to even-handed representation have led them to question the weak protection afforded to the standard of equality in the field of labour law that permits the enforcement of subsection 47.3. The Parry Sound decision handed down in 2003 could, however, usher in the era of a reverse trend.

Ce texte propose un modèle théorique permettant l’analyse d’expériences d’intégration socioprofessionnelle de personnes en situation d’itinérance. Ce modèle idéal type est construit à partir des études qui traitent du parcours de la personne itinérante et des organismes d’aide en réseau. S’intéressant à la fois à l’individu et à la structuration de l’action collective qui se déploie afin de favoriser l’intégration socioprofessionnelle, les auteurs proposent ensuite une conceptualisation du modèle à partir de l’institutionnalisme pragmatiste de J.R. Commons. This paper presents a theoretical model designed to study cases of socio-occupational integration involving homeless people. This ideal-type model is based on studies related to the career path followed by homeless people and to helping agencies that work together in a network. Dealing at the same time with the individual and with the structuring of collective action in order to facilitate socio-occupational integration, the authors then propose a conceptualization of the model based on J. R. Commons’ concept of pragmatist institutionalism.

Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.

A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2 nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays.

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

Protection by the -Pmb group is crucial for a successful transformation which needs neither microwave irradiation nor reflux conditions.

The aim of this study was to produce adjuvant with high biosafety, efficacy and low cost. Towards this goal, the plant Nicotiana benthamiana transient expression system was successfully used to express Salmonella typhimurium's flagellin (FljB). The yield of the expressed FljB was 280 mg per kg of fresh weight (FW) leaves. The lyophilized plant powder containing plant expressing FljB was mixed with ovalbumin (OVA) and used for oral immunization of BALB/c mice. The ELISA analysis showed higher and accelerated OVA-specific serum antibody responses in mice given the mixture when compared to animals receiving OVA alone. Furthermore, FljB elicited a mixed Th1/Th2 response as shown by the presence of specific anti-OVA IgG1, IgG2a and IgG2b isotypes. OVA-specific IgAs were also detected in mice given the mixture. Cell-mediated immune response to OVA was induced by FljB as determined by a spleen lymphocyte specific proliferation test. No immune response was generated against FljB. In conclusion, our results showed for the first time the production of FljB in plants and the efficient use of the crude lyophilized extract as an adjuvant for oral immunization.

A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compounds, 19a and 33b, were found to have K(i)'s of 20-30 nM against ML-IAP and 50-60 nM against XIAP-BIR3.

The INVIDO system is a graphical tool which was designed and implemented for studying user reactions to videotex systems. For different themes, including weather reporting, sport results and winning numbers in lotteries, different visual presentations have been created. As home visual information systems will invade the market in the next few years, it is essential to develop new tools which can give an idea of the user's reaction to this kind of information. The entire methodology (graphics capabilities, implementation and investigation) is presented. Numerous examples are also given.