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Generating comprehensive image maps, while preserving spatial three-dimensional (3D) context, is essential in order to locate and assess quantitatively specific cellular features and cell-cell interactions during organ development. Despite recent advances in 3D imaging approaches, our current knowledge of the spatial organization of distinct cell types in the embryonic pancreatic tissue is still largely based on two-dimensional histological sections. Here, we present a light-sheet fluorescence microscopy approach to image the pancreas in three dimensions and map tissue interactions at key time points in the mouse embryo. We demonstrate the utility of the approach by providing volumetric data, 3D distribution of three main cellular components (epithelial, mesenchymal and endothelial cells) within the developing pancreas, and quantification of their relative cellular abundance within the tissue. Interestingly, our 3D images show that endocrine cells are constantly and increasingly in contact with endothelial cells forming small vessels, whereas the interactions with mesenchymal cells decrease over time. These findings suggest distinct cell-cell interaction requirements for early endocrine cell specification and late differentiation. Lastly, we combine our image data in an open-source online repository (referred to as the Pancreas Embryonic Cell Atlas).
Assuntos
Imageamento Tridimensional/métodos , Pâncreas/anatomia & histologia , Animais , Embrião de Mamíferos/anatomia & histologia , Desenvolvimento Embrionário , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Epitélio/anatomia & histologia , Proteína Homeobox Nkx-2.5/deficiência , Proteína Homeobox Nkx-2.5/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de FluorescênciaRESUMO
A common developmental process, called branching morphogenesis, generates the epithelial trees in a variety of organs, including the lungs, kidneys, and glands. How branching morphogenesis can create epithelial architectures of very different shapes and functions remains elusive. In this review, we compare branching morphogenesis and its regulation in lungs and kidneys and discuss the role of signaling pathways, the mesenchyme, the extracellular matrix, and the cytoskeleton as potential organ-specific determinants of branch position, orientation, and shape. Identifying the determinants of branch and organ shape and their adaptation in different organs may reveal how a highly conserved developmental process can be adapted to different structural and functional frameworks and should provide important insights into epithelial morphogenesis and developmental disorders.
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During lung development, epithelial branches expand preferentially in a longitudinal direction. This bias in outgrowth has been linked to a bias in cell shape and in the cell division plane. How this bias arises is unknown. Here, we show that biased epithelial outgrowth occurs independent of the surrounding mesenchyme, of preferential turnover of the extracellular matrix at the bud tips and of FGF signalling. There is also no evidence for actin-rich filopodia at the bud tips. Rather, we find epithelial tubes to be collapsed during early lung and kidney development, and we observe fluid flow in the narrow tubes. By simulating the measured fluid flow inside segmented narrow epithelial tubes, we show that the shear stress levels on the apical surface are sufficient to explain the reported bias in cell shape and outgrowth. We use a cell-based vertex model to confirm that apical shear forces, unlike constricting forces, can give rise to both the observed bias in cell shapes and tube elongation. We conclude that shear stress may be a more general driver of biased tube elongation beyond its established role in angiogenesis. This article has an associated 'The people behind the papers' interview.
Assuntos
Fenômenos Biomecânicos , Rim/crescimento & desenvolvimento , Pulmão/crescimento & desenvolvimento , Organogênese , Animais , Biofísica , Forma Celular , Células Epiteliais/citologia , Matriz Extracelular , Feminino , Masculino , Mesoderma/metabolismo , Camundongos , Modelos Biológicos , Morfogênese , PseudópodesRESUMO
Branching patterns and regulatory networks differ between branched organs. It has remained unclear whether a common regulatory mechanism exists and how organ-specific patterns can emerge. Of all previously proposed signalling-based mechanisms, only a ligand-receptor-based Turing mechanism based on FGF10 and SHH quantitatively recapitulates the lung branching patterns. We now show that a GDNF-dependent ligand-receptor-based Turing mechanism quantitatively recapitulates branching of cultured wildtype and mutant ureteric buds, and achieves similar branching patterns when directing domain outgrowth in silico. We further predict and confirm experimentally that the kidney-specific positive feedback between WNT11 and GDNF permits the dense packing of ureteric tips. We conclude that the ligand-receptor based Turing mechanism presents a common regulatory mechanism for lungs and kidneys, despite the differences in the molecular implementation. Given its flexibility and robustness, we expect that the ligand-receptor-based Turing mechanism constitutes a likely general mechanism to guide branching morphogenesis and other symmetry breaks during organogenesis.
Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Rim/crescimento & desenvolvimento , Modelos Biológicos , Organogênese , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Wnt/metabolismo , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Simulação por Computador , Embrião de Mamíferos , Retroalimentação Fisiológica , Feminino , Processamento de Imagem Assistida por Computador , Rim/diagnóstico por imagem , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Técnicas de Cultura de Órgãos , Transdução de Sinais/fisiologia , Imagem com Lapso de Tempo/métodos , Tomografia Óptica/métodosRESUMO
The genes, XRS2 in Saccharomyces cerevisiae and NBN in mammals, have little sequence identity at the amino acid level. Nevertheless, they are both found together with MRE11 and RAD50 in a highly conserved protein complex which functions in the repair of DNA double-strand breaks. Here, we have examined the evolutionary and functional relationship of these two genes by cross-complementation experiments. These experiments necessitated sequence correction for specific codon usage before they could be successfully conducted. We present evidence that despite extreme sequence divergence nibrin can, at least partially, replace Xrs2 in the cellular DNA damage response, and Xrs2 is able to promote nuclear localization of MRE11 in NBS cells. We discuss that the extreme sequence divergence reflects a unique adaptive pressure during evolution related to the specific eukaryotic role for both Xrs2 and nibrin in the subcellular localisation of the DNA repair complex. This, we suggest, is of particular relevance when cells are infected by viruses. The conflict hypothesis of co-evolution of DNA repair genes and DNA viruses may thus explain the very low sequence identity of these two homologous genes.
Assuntos
Proteínas de Ciclo Celular , Códon , Dano ao DNA , Teste de Complementação Genética , Proteínas Nucleares , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Transformada , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Morphogenesis, the process by which an adult organism emerges from a single cell, has fascinated humans for a long time. Modeling this process can provide novel insights into development and the principles that orchestrate the developmental processes. This chapter focuses on the mathematical description and numerical simulation of developmental processes. In particular, we discuss the mathematical representation of morphogen and tissue dynamics on static and growing domains, as well as the corresponding tissue mechanics. In addition, we give an overview of numerical methods that are routinely used to solve the resulting systems of partial differential equations. These include the finite element method and the Lattice Boltzmann method for the discretization as well as the arbitrary Lagrangian-Eulerian method and the Diffuse-Domain method to numerically treat deforming domains.
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Simulação por Computador , Desenvolvimento Embrionário , Análise de Elementos Finitos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Algoritmos , Animais , Proliferação de Células , Modelos Biológicos , Morfogênese , Transdução de SinaisRESUMO
Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm predominantly occurring in the soft tissue. A majority of EHE cases is driven by a WW domain containing transcription regulator protein 1 (WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) gene fusion. The clinical course of EHE ranges from long-term favorable to rapidly aggressive. Few cases of intracranial EHE have been reported, none of which has been molecularly proven. We report a case of left parietal meningeal EHE, which was resected 15 years after initial radiological detection. Four years prior to surgery, a second atlantooccipital lesion and pulmonary nodules were detected, which remained constant in subsequent radiological controls. The tumor infiltrated the cranial bone. Histology showed an isomorphic tumor with epithelioid cells forming vacuoles that contained erythrocytes. Necrosis was absent and anaplasia and proliferative activity were scant. Immunohistochemistry showed expression of the endothelial markers CD34, CD31, vascular endothelial growth factor, and factor VIII and predominantly nuclear overexpression of CAMTA1. Fluorescence in situ hybridization showed WWTR1-CAMTA1 gene fusion. Our report provides the first case of intracranial EHE with molecular proof of WWTR1-CAMTA1 gene fusion. The slowly progressive clinical course of 15 years is the longest so far reported for intracranial EHE.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Proteínas de Ligação ao Cálcio , Rearranjo Gênico , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Meníngeas/diagnóstico por imagem , Transativadores , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Proteínas de Ligação ao Cálcio/genética , Rearranjo Gênico/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/cirurgia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/cirurgia , Pessoa de Meia-Idade , Transativadores/genética , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Carga Tumoral/genéticaRESUMO
Many organs require a high surface to volume ratio to properly function. Lungs and kidneys, for example, achieve this by creating highly branched tubular structures during a developmental process called branching morphogenesis. The genes that control lung and kidney branching share a similar network structure that is based on ligand-receptor reciprocal signalling interactions between the epithelium and the surrounding mesenchyme. Nevertheless, the temporal and spatial development of the branched epithelial trees differs, resulting in organs of distinct shape and size. In the embryonic lung, branching morphogenesis highly depends on FGF10 signalling, whereas GDNF is the driving morphogen in the kidney. Knockout of Fgf10 and Gdnf leads to lung and kidney agenesis, respectively. However, FGF10 plays a significant role during kidney branching and both the FGF10 and GDNF pathway converge on the transcription factors ETV4/5. Although the involved signalling proteins have been defined, the underlying mechanism that controls lung and kidney branching morphogenesis is still elusive. A wide range of modelling approaches exists that differ not only in the mathematical framework (e.g., stochastic or deterministic) but also in the spatial scale (e.g., cell or tissue level). Due to advancing imaging techniques, image-based modelling approaches have proven to be a valuable method for investigating the control of branching events with respect to organ-specific properties. Here, we review several mathematical models on lung and kidney branching morphogenesis and suggest that a ligand-receptor-based Turing model represents a potential candidate for a general but also adaptive mechanism to control branching morphogenesis during development.
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Zinc is a crucial mineral for all organisms as it is an essential cofactor for the proper function of a plethora of proteins and depletion of zinc causes oxidative stress. Glutathione is the major redox buffering agent in the cell and therefore important for mitigation of the adverse effects of oxidative stress. In mammalian cells, zinc deficiency is accompanied by a glutathione depletion. In the yeast Saccharomyces cerevisiae, the opposite effect is observed: under low zinc conditions, an elevated glutathione concentration is found. The main regulator to overcome zinc deficiency is Zap1p. However, we show that Zap1p is not involved in this glutathione accumulation phenotype. Furthermore, we found that in glutathione-accumulating strains also the metal ion-binding phytochelatin-2, which is an oligomer of glutathione, is accumulated. This increased phytochelatin concentration correlates with a lower free zinc level in the vacuole. These results suggest that phytochelatin is important for zinc buffering in S. cerevisiae and thus explains how zinc homeostasis is connected with glutathione metabolism.
Assuntos
Glutationa/metabolismo , Homeostase , Fitoquelatinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Zinco/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Saccharomyces cerevisiae is a popular expression system for recombinant proteins. In most cases, production processes are performed as carbon-limited fed-batch cultures to avoid aerobic ethanol formation. Especially for constitutive expression systems, the specific product formation rate depends on the specific growth rate. The development of optimal feeding strategies strongly depends on laboratory-scale cultivations, which are time and resource consuming, especially when continuous experiments are carried out. It is therefore beneficial for accelerated process development to look at alternatives. In this study, S. cerevisiae AH22 secreting a heterologous endo-polygalacturonase (EPG) was characterized in microwell plates with an enzyme-based fed-batch medium. Through variation of the glucose release rate, different growth profiles were established and the impact on EPG secretion was analyzed. Product formation rates of 200-400 U (gx h)-1 were determined. As a reference, bioreactor experiments using the change-stat cultivation technique were performed. The growth-dependent product formation was analyzed over dilution rates of D = 0.01-0.35 with smooth change of D at a rate of 0.003 h-2. EPG production was found to be comparable with a qp of 400 U (gx h)-1 at D = 0.27 h-1. The presented results indicate that parallel miniaturized fed-batch cultures can be applied to determine product formation profiles of putative production strains. With further automation and parallelization of the concept, strain characterization can be performed in shorter time.
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Agricultura/economia , Biocombustíveis/economia , Biotecnologia/economia , Conservação dos Recursos Naturais/economia , Objetivos , Internacionalidade , Congressos como Assunto , Conservação dos Recursos Naturais/tendências , Abastecimento de Alimentos/economia , Agricultura Florestal/economia , Química Verde/economia , Humanos , Saúde Pública , Inanição/prevenção & controle , Abastecimento de Água/economiaRESUMO
Glutathione is an important natural tripeptide mainly used because of its antioxidative properties. Commercial glutathione is microbially synthesized by yeasts and the growing demand requires the development of new production strains. An adaptive laboratory evolution strategy using acrolein as a selection agent was employed to obtain strains with an enhanced glutathione accumulation phenotype accompanied by an acrolein resistance phenotype. Two particularly interesting isolates were obtained: one with a high volumetric productivity for glutathione reaching 8.3 mg(glutathione)/L h, which is twice as high as the volumetric productivity of its parental strain. This strain reached an elevated intracellular glutathione content of 3.9%. A second isolate with an even higher acrolein tolerance exhibited a lower volumetric productivity of 5.8 mg(glutathione)/L h due to a growth phenotype. However, this evolved strain accumulated glutathione in 3.3-fold higher concentration compared to its parental strain and reached a particularly high glutathione content of almost 6%. The presented results demonstrate that acrolein is a powerful selection agent to obtain high glutathione accumulation strains in an adaptive laboratory evolution experiment.
Assuntos
Glutationa/metabolismo , Engenharia Metabólica/métodos , Saccharomyces cerevisiae/metabolismo , Reatores Biológicos , Evolução Molecular Direcionada , Etanol , Glutationa/análise , Saccharomyces cerevisiae/genéticaRESUMO
In this study, a slow-responding chemo-optical sensor for dissolved oxygen (DO) integrated into a 96-well plate was developed. The slow response time ensures that the measured oxygen value does not change much during plate transport to the microplate reader. The sensor therefore permits at-line DO measurement of microbial cultures. Moreover, it eliminates the necessity of individual optical measurement systems for each culture plate, as many plates can be measured successively. Combined with the 96-well format, this increases the experimental throughput enormously. The novel sensor plate (Slow OxoPlate) consists of fluorophores suspended in a polymer matrix that were placed into u-bottom 96-well plates. Response time was measured using sodium sulfite, and a t90 value of 9.7 min was recorded. For application, DO values were then measured in Escherichia coli and Saccharomyces cerevisiae cultures grown under fed-batch-like conditions. Depending on the DO sensor's response time, different information on the oxygenation state of the culture plate was obtained: a fast sensor variant detects disturbance through sampling, whereas the slow sensor indicates oxygen limitation during incubation. A combination of the commercially available OxoPlate and the Slow OxoPlate enables operators of screening facilities to validate their cultivation procedures with regard to oxygen availability.
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Reatores Biológicos/microbiologia , Biotecnologia/instrumentação , Ensaios de Triagem em Larga Escala/instrumentação , Oxigênio/análise , Biotecnologia/métodos , Desenho de Equipamento , Corantes Fluorescentes/análise , Corantes Fluorescentes/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Oxigênio/metabolismoRESUMO
Identification of patients with increased risk of 5-fluorouracil (5-FU)-related toxicity is an important challenge for cancer treatment. Research often focus on dihydropyrimidine dehydrogenase (DPYD) deficiency in this context. However, patients with normal DPYD activity may also develop life-threatening 5-FU adverse effects. DPYD initiates the catabolic route of 5-FU generating metabolites such as fluoroacetate (FAC). The catabolite FAC is known to inhibit the TCA cycle enzyme aconitase, which is supposed to impair mitochondrial energy metabolism. Therefore, we aim for a systems understanding of the association of 5-FU-related cardiac side effects with aconitase inhibition caused by FAC. Using a mitochondrial model of cardiomyocytes we found strong depletion of ATP production and citrate accumulation as main effects of aconitase inhibition. Shadow price analysis revealed that the uptakes of valine, arginine, proline and glutamate are most effective in compensating the impairment of energy metabolism. Our findings suggest that 5-FU catabolism contributes to the occurrence of cardiac adverse effects and are the basis for further biomarker identifications and development of side effect treatment.
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Aminoácidos/administração & dosagem , Aminoácidos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Fluoruracila/farmacologia , Miócitos Cardíacos/metabolismo , Aconitato Hidratase/antagonistas & inibidores , Aconitato Hidratase/metabolismo , Trifosfato de Adenosina/metabolismo , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Oxigênio/metabolismoRESUMO
Reducing the amount of Helicobacter pylori in the stomach by selective bacterial-bacterial cell interaction was sought as an effective and novel method for combating the stomach pathogen. Lactobacillus reuteri DSM17648 was identified as a highly specific binding antagonist to H. pylori among more than 700 wild-type strains of Lactobacillus species. Applying a stringent screening procedure, the strain DSM17648 was identified as selective binder to H. pylori cells under in vivo gastric conditions. The strain DSM17648 co-aggregates the pathogen in vivo and in vitro. The specific co-aggregation occurs between Lact. reuteri DSM17648 and different H. pylori strains and serotypes, as well as H. heilmannii, but not with Campylobacter jejuni or other commensal oral and intestinal bacteria. Lact. reuteri DSM17648 was shown in a proof-of-concept single-blinded, randomized, placebo-controlled pilot study to significantly reduce the load of H. pylori in healthy yet infected adults. Reducing the amount of H. pylori in the stomach by selective bacterial-bacterial cell interaction might be an effective and novel method for combating the stomach pathogen. Lact. reuteri DSM17648 might prove useful as an adhesion blocker in antibiotic-free H. pylori therapies.
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Carga Bacteriana , Infecções por Helicobacter/terapia , Helicobacter pylori/patogenicidade , Limosilactobacillus reuteri/fisiologia , Adolescente , Campylobacter jejuni/patogenicidade , Estudos Cross-Over , Microbioma Gastrointestinal , Humanos , Modelos Lineares , Projetos Piloto , Probióticos/administração & dosagem , Método Simples-Cego , Estômago/microbiologiaRESUMO
A 21-year-old man presented with headache, hypotonia, hypothermia, and somnolence, deteriorating to a Glasgow Coma Scale score of 3 within days. Hormonal testing revealed panhypopituitarism. His cerebral MRI showed a gadolinium-enhancing lesion in the pituitary gland with adjacent changes to the hypothalamus, midbrain, and basal ganglia (figures 1 and 2). Therapy with prednisolone resulted in rapid improvement. Ma2 antibodies were found in the patient's serum and CSF. FDG-PET demonstrated a tumor mass in the superior mediastinum and histology revealed a mediastinal seminoma. Ma2 antibody-mediated paraneoplastic disease has to be considered as a rare differential diagnosis in patients presenting with acute panhypopituitarism.(1.)
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Antígenos de Neoplasias/metabolismo , Encefalite/diagnóstico , Hipopituitarismo/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Córtex Cerebral/patologia , Encefalite/líquido cefalorraquidiano , Encefalite/diagnóstico por imagem , Fluordesoxiglucose F18 , Escala de Coma de Glasgow , Humanos , Hipopituitarismo/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Hipófise/patologia , Tomografia por Emissão de Pósitrons , Adulto JovemRESUMO
Reducing the burden of pathogenic mutans streptococci is a goal of oral health. Lactobacillus paracasei DSMZ16671, even after heat-killing, specifically co-aggregates mutans streptococci in vitro and retains this activity in human saliva. In rats, it reduces mutans streptococcal colonization of teeth and caries scores. This pilot study sought to assess the potential of heat-killed L. paracasei DSMZ16671 (pro-t-action®) to reduce levels of salivary mutans streptococci in humans, using sugar-free candies as a delivery vehicle. A randomized, placebo-controlled, double-blind in vivo study of three groups examined the short-term effect of sugar-free candies containing 0 (placebo), 1, or 2 mg/candy piece of heat-killed L. paracasei DSMZ16671 on the levels of salivary mutans streptococci determined before and after consumption of the candies. The candies were consumed 4 times during 1.5 consecutive days. Compared to the placebo group, the test groups' saliva had significantly reduced mutans streptococci as an immediate effect. These results suggest the use of heat-killed L. paracasei DSMZ16671 in suckable candies as a method to reduce mutans streptococci in the mouth and, thereby, caries risk. We think this a new concept and strategy for caries prevention and management.
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Fígado Gorduroso/diagnóstico , Fígado Gorduroso/epidemiologia , Adulto , Biópsia , Comorbidade , Diagnóstico Diferencial , Fígado Gorduroso/mortalidade , Fígado Gorduroso/terapia , Fígado Gorduroso Alcoólico/diagnóstico , Fígado Gorduroso Alcoólico/epidemiologia , Fígado Gorduroso Alcoólico/mortalidade , Fígado Gorduroso Alcoólico/terapia , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/mortalidade , Cirrose Hepática/terapia , Testes de Função Hepática , Masculino , Hepatopatia Gordurosa não Alcoólica , Prognóstico , Análise de Sobrevida , Taxa de Sobrevida , UltrassonografiaRESUMO
Saccharomyces cerevisiae strains with deregulated sterol and fatty acid biosynthesis pathways were analysed for sterol and fatty acid content and mRNA profiles, with the aim of identifying interactions between lipid biosynthesis pathways. Acetyl CoA carboxylase ACC1 and fatty acid synthases FAS1/FAS2 were overexpressed in wild-type and squalene-overproducing strains. ACC1 overexpression led to decreased fatty acid content in the squalene-overproducing strain (factor of 0.7), while sterols and squalene were increased (factor of 1.5). In the wild-type strain, ACC1 overexpression led to increased levels of both fatty acids and squalene/sterols (factors of 4.0 and 1.7, respectively). This parallel activation of the two pathways seems to be due to transcriptional co-regulation of ACC1 and HMG1. While FAS1 and FAS2 overexpression had no effect in the wild-type strain, FAS2 overexpression induced significant increase of sterols and squalene (factors of 7.2 and 1.3, respectively) and a concomitant decrease of both saturated and unsaturated fatty acids in the squalene-overproducing strain (factor of 0.6). The microarray expression profiles showed that genes upregulated in ACC1-overexpressing strains are FAS1, ERG11, ERG28, ERG5, ERG2 and ERG20, supporting the observed increase of zymosterol and saturated fatty acids. The high ACC1 expression level due to overexpression correlated with increased transcript levels of sphingolipid and sterol biosynthesis genes. The relationship between was shown using the Pathway Studio program.