Development of a 3D atlas of the embryonic pancreas for topological and quantitative analysis of heterologous cell interactions.

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).

The biomechanical basis of biased epithelial tube elongation in lung and kidney development.

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.

SBML Level 3: an extensible format for the exchange and reuse of biological models.

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

Effects of two bisbenzylisoquinoline alkaloids, Antioquine and Tetrandrine, compared to Verapamil in Rat Thoracic Aorta.

The objective of this study was to compare two alkaloids (antioquine and tetrandrine) with verapamil; knowing that the smooth muscle respond to KCl and relationships with calcium. The effects of antioquine and tetrandrine, was studied in adults Wistar rat with modified methods used in the determination of aorta contractility and compared with verapamil effect in the same assays. The analysis of the effect of a drug or extract on aortic reactivity included maximal relaxation or maximal contraction (Cmax) (Phase 1). In our results, verapamil induced a blockade of 98.7 ± 0.7% (n = 6) in presence of endothelium and 97.9 ± 4.3% in ausence of endothelium, both in phase 1 and in phase 2 of 47.4 ± 4.1% (n = 6) in aortas in the presence of endothelium and 61.8 ± 1.1% in ausence of endothelium; Tetrandrine assays showed a phase 1 blocking effect of 63.4 ± 5.5 and 47.7 ± 2.9% (with and without endothelium, respectively) and phase 2 of 43.5 ± 6.2 and 28.5 ± 5.7%, (with and without endothelium, respectively). Antioquine presents in phase 1 and phase 2, a blockade that is not significant from the point of view of calcium antagonism. We can conclude that tetrandrine block the movement of calcium from both intracellular and extracellular deposits, with the greatest effect when aortas are in the presence of endothelium.

MOCCASIN: converting MATLAB ODE models to SBML.

UNLABELLED: MATLAB is popular in biological research for creating and simulating models that use ordinary differential equations (ODEs). However, sharing or using these models outside of MATLAB is often problematic. A community standard such as Systems Biology Markup Language (SBML) can serve as a neutral exchange format, but translating models from MATLAB to SBML can be challenging-especially for legacy models not written with translation in mind. We developed MOCCASIN (Model ODE Converter for Creating Automated SBML INteroperability) to help. MOCCASIN can convert ODE-based MATLAB models of biochemical reaction networks into the SBML format. AVAILABILITY AND IMPLEMENTATION: MOCCASIN is available under the terms of the LGPL 2.1 license (http://www.gnu.org/licenses/lgpl-2.1.html). Source code, binaries and test cases can be freely obtained from https://github.com/sbmlteam/moccasin CONTACT: : mhucka@caltech.edu SUPPLEMENTARY INFORMATION: More information is available at https://github.com/sbmlteam/moccasin.

JSBML 1.0: providing a smorgasbord of options to encode systems biology models.

UNLABELLED: JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users. AVAILABILITY AND IMPLEMENTATION: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/. CONTACT: jsbml-development@googlegroups.com or andraeger@eng.ucsd.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Sucrose esters from Physalis peruviana calyces with anti-inflammatory activity.

Physalis peruviana is a native plant from the South American Andes and is widely used in traditional Colombian medicine of as an anti-inflammatory medicinal plant, specifically the leaves, calyces, and small stems in poultice form. Previous studies performed by our group on P. peruviana calyces showed potent anti-inflammatory activity in an enriched fraction obtained from an ether total extract. The objective of the present study was to obtain and elucidate the active compounds from this fraction and evaluate their anti-inflammatory activity in vivo and in vitro. The enriched fraction of P. peruviana was purified by several chromatographic methods to obtain an inseparable mixture of two new sucrose esters named peruviose A (1) and peruviose B (2). Structures of the new compounds were elucidated using spectroscopic methods and chemical transformations. The anti-inflammatory activity of the peruvioses mixture was evaluated using λ-carrageenan-induced paw edema in rats and lipopolysaccharide-activated peritoneal macrophages. Results showed that the peruvioses did not produce side effects on the liver and kidneys and significantly attenuated the inflammation induced by λ-carrageenan in a dosage-dependent manner, probably due to an inhibition of nitric oxide and prostaglandin E2, which was demonstrated in vitro. To our knowledge, this is the first report of the presence of sucrose esters in P. peruviana that showed a potent anti-inflammatory effect. These results suggest the potential of sucrose esters from the Physalis genus as a novel natural alternative to treat inflammatory diseases.

nEASE: a method for gene ontology subclassification of high-throughput gene expression data.

UNLABELLED: High-throughput technologies can identify genes whose expression profiles correlate with specific phenotypes; however, placing these genes into a biological context remains challenging. To help address this issue, we developed nested Expression Analysis Systematic Explorer (nEASE). nEASE complements traditional gene ontology enrichment approaches by determining statistically enriched gene ontology subterms within a list of genes based on co-annotation. Here, we overview an open-source software version of the nEASE algorithm. nEASE can be used either stand-alone or as part of a pathway discovery pipeline. AVAILABILITY: nEASE is implemented within the Multiple Experiment Viewer software package available at http://www.tm4.org/mev. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Time-lapse and cleared imaging of mouse embryonic lung explants to study three-dimensional cell morphology and topology dynamics.

Here, we present a protocol for collecting high-spatiotemporal-resolution datasets of undisturbed mouse embryonic epithelial rudiments using light-sheet fluorescence microscopy. We describe steps for rudiment dissection, clearing, and embedding for cleared and live imaging. We then detail procedures for light-sheet imaging followed by image processing and morphometric analysis. We provide protocol variations for imaging both growing and optically cleared lung explants to encourage the quantitative exploration of three-dimensional cell shapes, cell organization, and complex cell-cell dynamics. For complete details on the use and execution of this protocol, please refer to Gómez et al. (2021).1.

Clinical and Biomarker Responses to BI 655064, an Antagonistic Anti-CD40 Antibody, in Patients With Active Lupus Nephritis: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial.

OBJECTIVE: To characterize its dose-response relationship, BI 655064 (an anti-CD40 monoclonal antibody) was tested as an add-on to mycophenolate and glucocorticoids in patients with active lupus nephritis (LN). METHODS: A total of 121 patients were randomized (2:1:1:2) to receive placebo or BI 655064 120, 180, or 240 mg and received a weekly loading dose for 3 weeks followed by dosing every 2 weeks for the 120 and 180 mg groups, and 120 mg weekly for the 240 mg group. The primary endpoint was complete renal response (CRR) at week 52. Secondary endpoints included CRR at week 26. RESULTS: A dose-response relationship with CRR at week 52 was not shown (BI 655064 120 mg, 38.3%; 180 mg, 45.0%; 240 mg, 44.6%; placebo, 48.3%). At week 26, 28.6% (120 mg), 50.0% (180 mg), 35.0% (240 mg), and 37.5% (placebo) achieved CRR. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR, at weeks 46 and 52). cCRR was achieved in 22.5% (120 mg), 44.3% (180 mg), 38.2% (240 mg), and 29.1% (placebo) of patients. Most patients reported ≥1 adverse event (BI 655064, 85.7-95.0%; placebo, 97.5%), most frequently infections and infestations (BI 655064 61.9-75.0%; placebo 60%). Compared with other groups, higher rates of serious (20% vs. 7.5-10%) and severe infections (10% vs. 4.8-5.0%) were reported with 240 mg BI 655064. CONCLUSION: The trial failed to demonstrate a dose-response relationship for the primary CRR endpoint. Post hoc analyses suggest a potential benefit of BI 655064 180 mg in patients with active LN.

Morphological study of embryonic Chd8+/- mouse brains using light-sheet microscopy.

OBJECTIVE: Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions that remain poorly understood due to their genetic complexity. CHD8 is a risk allele strongly associated with ASD, and heterozygous Chd8 loss-of-function mice have been reported to exhibit macrocephaly in early postnatal stages. In this work, we sought to identify measurable brain alterations in early embryonic development. RESULTS: We performed light-sheet fluorescence microscopy imaging of N-cadherin stained and optically cleared Chd8+/- and wild-type mouse brains at embryonic day 12.5 (E12.5). We report a detailed morphometric characterization of embryonic brain shapes and cortical neuroepithelial apical architecture. While Chd8+/- characteristic expansion of the forebrain and midbrain was not observed this early in embryogenesis, a tendency for a decreased lateral ventricular sphericity and an increased intraocular distance in Chd8+/- brains was found compared to controls. This study advocates the use of high-resolution microscopy technologies and multi-scale morphometric analyses of target brain regions to explore the etiology and cellular basis of Chd8 haploinsufficiency.

3D cell neighbour dynamics in growing pseudostratified epithelia.

During morphogenesis, epithelial sheets remodel into complex geometries. How cells dynamically organise their contact with neighbouring cells in these tightly packed tissues is poorly understood. We have used light-sheet microscopy of growing mouse embryonic lung explants, three-dimensional cell segmentation, and physical theory to unravel the principles behind 3D cell organisation in growing pseudostratified epithelia. We find that cells have highly irregular 3D shapes and exhibit numerous neighbour intercalations along the apical-basal axis as well as over time. Despite the fluidic nature, the cell packing configurations follow fundamental relationships previously described for apical epithelial layers, that is, Euler's polyhedron formula, Lewis' law, and Aboav-Weaire's law, at all times and across the entire tissue thickness. This arrangement minimises the lateral cell-cell surface energy for a given cross-sectional area variability, generated primarily by the distribution and movement of nuclei. We conclude that the complex 3D cell organisation in growing epithelia emerges from simple physical principles.

Toward Community Standards and Software for Whole-Cell Modeling.

OBJECTIVE: Whole-cell (WC) modeling is a promising tool for biological research, bioengineering, and medicine. However, substantial work remains to create accurate comprehensive models of complex cells. METHODS: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in the Systems Biology Markup Language. RESULTS: Our analysis revealed several challenges to representing WC models using the current standards. CONCLUSION: We, therefore, propose several new WC modeling standards, software, and databases. SIGNIFICANCE: We anticipate that these new standards and software will enable more comprehensive models.

Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.

BACKGROUND: Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity. RESULTS: In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors. CONCLUSION: Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure.

La importancia del conocimiento en el hospital / The Importance of the Knowledge in the Hospital / A importância do conhecimento no hospital

Introducción: El conocimiento en el hospital representa la mejor oportunidad para fortalecer la institución con mejores decisiones y posibilita una de las formas de sostenibilidad financiera. Objetivo: El presente artículo tiene como objetivo dar a conocer la experiencia de un hospital público de II Nivel en Bogotá, que instaura el proceso de gestión del conocimiento. Eso significa que avanza en el desarrollo de la investigación, la construcción de estrategias de sistematización de experiencias, la protección de la propiedad intelectual y el uso social del conocimiento por mecanismos diseñados para transferirlo. Métodos: Se documenta la implementación del macroproceso de gestión del conocimiento entre junio de 2012 y junio de 2015, mediante la normalización del proceso y los subprocesos, el desarrollo de alianzas estratégicas con universidades como la Universidad de los Andes y la Universidad Nacional de Colombia, para robustecer los procesos del hospital en la planeación, en lo misional y en la propia gestión institucional de proyección a la comunidad, en la atención y, en especial, en la toma de las decisiones basadas en la evidencia. Resultados: La gestión del conocimiento le ha permitido al hospital objeto de estudio avanzar en investigación definiendo una política institucional, líneas de investigación, la conformación de un semillero y la creación de un grupo de investigación. Así mismo, se cuenta con estrategias de transferencia y uso social. Conclusiones: Se debe avanzar en la construcción del macroproceso, con acciones de mejora continua, así como la proyección de la gestión del conocimiento en los diferentes ámbitos de desarrollo institucional.

Introduction: The knowledge in the hospital represents the best opportunity to strengthen the institution with better decisions and makes one of the forms possible of financial sustainability. Objetive: The Present article has as aim announce the experience of a public hospital of the II Level in Bogota, which restores the process of management of the knowledge. It means that it advances in the development of the investigation, the construcción of strategies of systematizing experience, the protection of the intellectual property and the social use of the knowledge for mechanisms designed to transfer it. Methods: there receives documents the implementation of the macroprocess of management of the knowledge between June, 2012 and June, 2015, by means of the normalization of the process and the subprocesses, the development of strategic alliances with universities like the University of the Andes and the National University of Colombia, for robustecer the processes of the hospital in the planeación, in misional and in the own institutional management of projection to the community, in the attention and, especially, in the capture of the decisions based on the evidence. Results: The management of the knowledge has allowed him the hospital object of study to advance in investigation defining an institutional politics, lines of investigation, the conformation of a seedbed and the creation of a group of investigation. Likewise, one possesses strategies of transfer and social use. Conclusions: it is necessary to to advance in the construction of the macroprocess, with actions of constant improvement, as well as the projection of the management of the knowledge in the different areas of institution building. Key words: management of the knowledge, methodological model, I macroprocess.

Introdução: O conhecimento no hospital representa a melhor oportunidade para fortalecer a instituição com decisões melhores e um dos modos de sostenibilidad financeiro facilita. Objetivo: O artigo presente tem como objetivo para dar para saber a experiência de um hospital público de II Nivelado em Bogotá que estabelece o processo de administração do conhecimento. Isso significa que avança no desenvolvimento da investigação, o sconstrucción de estratégias de sistematizar de experiências, que a proteção da propriedade intelectual e o uso social do conhecimento para mecanismos projetou para transferir isto. Métodos: A implementação do macroproceso de administração do conhecimento é documentada entre junho de 2012 e junho de 2015, por meio da normalização do processo e o subprocesos, o desenvolvimento de alianças estratégicas com universidades como a Universidade de Andes e a Universidade Nacional de Colômbia, fortalecer os processos do hospital no planeación, no misional e na própria administração institucional de projeção para a comunidade, na atenção especialmente, na tomada das decisões fundada na evidência. Resultados: A administração do conhecimento permitiu ao objeto de estudo de hospital avançar em investigação que define umas políticas institucionais, linhas de investigação, a conformação de um berçário e a criação de um grupo de investigação. Igualmente, é tido estratégias de transferência e uso social. Conclusões: Você deveria avançar na construção do macroproceso, com ações de melhoria contínua, como também a projeção da administração do conhecimento nos ambientes diferentes de desenvolvimento institucional.

Tocilizumab treatment of rheumatoid arthritis among Filipino patients

Introduction. Studies have shown that tocilizumab (TCZ) is effective in the treatment of rheumatoid arthritis. This study examined the efficacy and safety of TCZ in Filipino patients with moderate to severe rheumatoid arthritis (RA). Methods. This was an open-label, one-arm clinical trial approved by the Philippine Council Health Research Development-National Ethics Committee (PCHRD-NEC), among moderate-severe active RA Filipino patients in 4 RA clinics. The study consisted of a 28-day screening-baseline period; a 24-week treatment period, with once every-4-weeks TCZ 8mg/kg intravenous infusion (IV) and an efficacy-safety evaluation. Patients already receiving methotrexate (MTX) at study entry went on with MTX plus TCZ per medical discretion. Descriptive statistics computed for physician's and patient's global assessment of disease activity, patient's global assessment of pain, ACR20, ACR50 and ACR70. Analysis of variance (ANOVA) determined significant changes over time for DAS-28 ESR, FACIT and HAQ-DI fatigue scores. Twenty-nine of thirty patients were included in efficacy and safety analysis. Results. After 24 weeks of TCZ: 86%, 66%, and 48% of 29 Filipino RA patients achieved ACR20, ACR50, ACR70, respectively, with 34% achieving remission according to DAS28-ESR. Median times to first achieving ACR20, ACR50 and ACR70 were 4, 12, and 24 weeks, respectively. There were also significant rapid reductions in physician's and patient's global assessment of disease activity, patient's global assessment of pain, HAQ-DI and FACIT scores noted over time. Tolerability profile was similar to published literature on TCZ. Conclusions. TCZ has been shown to be effective in the treatment of Filipino patients with moderate to severe rheumatoid arthritis. TCZ can be given in an out-patient RA clinic setting.