Agile Beeswax: Mobile App Development Process and Empirical Study in Real Environment

Mobile application development is a highly competitive environment; agile methodologies can enable teams to provide value faster, with higher quality and predictability, and a better attitude to deal with the continuous changes that will arise in the mobile context application (App), and the positive impact of that on sustainable development through continuous progress. App development is different from other types of software. For this reason, our objective is to present a new agilebased methodology for app development that we call Agile Beeswax. Agile Beeswax is conceived after identifying the mobile development process’s issues and challenges, and unique requirements. Agile Beeswax is an incremental, iterative development process composed of two main iterative loops (sprints), the incremental design loop and the incremental development loop, and one bridge connecting these two sprints. Agile Beeswax is structured in six phases, idea and strategy, user experience design, user interface design, design to development, handoff and technical decisions, development, and deployment and monitoring. One of its main strengths is that it has been created with academic and business perspectives to bring these two communities closer. To achieve this purpose, our research methodology comprises four main phases: Phase 1: Extensive literature review of mobile development methodologies, Phase 2: Interviews with mobile application developers working in small to medium software companies, Phase 3: Survey to extract valuable knowledge about mobile development (which was carefully designed based on the results of the first and the second phases), and Phase 4: Proposal of a new methodology for the agile development of mobile applications. With the aim of integrating both perspectives, the survey was answered by a sample of 35 experts, including academics and developers. Interesting results have been collected and discussed in this paper (on issues such as the development process, the tools used during this process, and the general issues and challenges they encountered), laying the foundations of the methodology Agile Beeswax proposed to develop mobile apps. Our results and the proposed methodology are intended to serve as support for mobile application developers.Spanish Government European Commission RTI2018-096986-B-C3

α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies

Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson´s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe´s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.Fil: Abdelkarim, Hazem. University of Illinois; Estados UnidosFil: Marshall, Michael S.. University of Illinois; Estados UnidosFil: Scesa, Giuseppe. University of Illinois; Estados UnidosFil: Smith, Rachael A.. University of Illinois; Estados UnidosFil: Rue, Emily. University of Illinois; Estados UnidosFil: Marshall, Jeffrey. University of Illinois; Estados UnidosFil: Elackattu, Vince. University Of Illinois Chicago; Estados UnidosFil: Stoskute, Monika. University Of Illinois Chicago; Estados UnidosFil: Issa, Yazan. University Of Illinois Chicago; Estados UnidosFil: Santos, Marta. University Of Illinois Chicago; Estados UnidosFil: Nguyen, Duc. University Of Illinois Chicago; Estados UnidosFil: Hauck, Zane. University Of Illinois Chicago; Estados UnidosFil: Van Breemen, Richard B.. University Of Illinois Chicago; Estados UnidosFil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Gaponenko, Vadim. University Of Illinois Chicago; Estados UnidosFil: Bongarzone, Ernesto R.. University Of Illinois Chicago; Estados Unido

Novel Peptide Nanoparticle Biased Antagonist of CCR3 Blocks Eosinophil Recruitment and Airway Hyperresponsiveness

Background—Chemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason may be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance. Objective—We sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G-protein signaling, but enable or promote receptor internalization. Methods—Self-assembly of R321 peptide into nanoparticles and peptide binding to CCR3 were analyzed by dynamic light scattering and NMR. Inhibitory activity on CCR3 signaling was assessed in vitro using flow cytometry, confocal microscopy, and western blot analysis in a CCR3+ eosinophil cell line and blood eosinophils. In vivo effects of R321 were assessed using a triple allergen mouse asthma model. Results—R321 self-assembles into nanoparticles and binds directly to CCR3, altering receptor function. IC50 values for eotaxin-induced chemotaxis of blood eosinophils are in the low nanomolar range. R321 inhibits only the early phase of ERK1/2 activation and not the late phase generally associated with β-arrestin recruitment and receptor endocytosis, promoting CCR3 internalization and degradation. In vivo, R321 effectively blocks eosinophil recruitment into the lungs and airways and prevents airway hyperresponsiveness in a mouse eosinophilic asthma model. Conclusions—R321 is a potent and selective antagonist of the CCR3 signaling cascade. Inhibition through a biased mode of antagonism may hold significant therapeutic promise by eluding the formation of drug tolerance

Agile Beeswax: Agile Development Methodology for Mobile Applications

Mobile applications have seen great development in recent years, and with this growth, tools, phones, and methods of developing these applications have evolved. However, the methods of developing these mobile applications have not seen the same growth as its usage. Software engineering research on mobile application development methodologies is not progressing at the same rate as the adoption of mobile applications. Only a few mobile application development methodologies have been presented in the scientific literature, especially agile ones. In addition, mobile application idea and concept workshops, requirements gathering, User Interface, User Experience, deployment, maintenance, complexity of testing, power consumption, and project assessment activities receive very little attention from existing methodologies. Moreover, in the current proposals are not sufficiently handling the special limitations for mobile applications, such as providing the necessary features to facilitate and support users' participation in the development process. After extensive study in academia and industry, in our opinion it indisputable that the research into the mobile application development process must continue to grow. Mobile application development is a highly competitive environment, and in our opinion, agile methodologies can enable teams to provide value faster, with higher quality and predictability. The development of mobile applications has unique requirements, and agile methods can deal with some of these requirements, such as the continuous change in mobile applications requirements or the continuous participation of users. An efficient development process may assist increase competitive advantage and decreasing release cycles. For this reason, our objective has been to review the existing methodologies and models for developing mobile applications in the scientific literature and real methodologies adopted by experts in the development communities since this will help us address the main practices in the mobile application development process. Based on a defined and appropriate frame, an analysis of these models and their usefulness to the industry has been performed to create a new methodology for developing mobile applications that suit academic and industry communities. This new methodological process based on agile methodologies for mobile application development has been named Agile Beeswax. Thus, Agile Beeswax is conceived after identifying the mobile development process's issues, challenges, and unique requirements. Agile Beeswax is defined as an integrated incremental, iterative development process for developing mobile applications. One of its main strengths is that it has been created with academic and business perspectives to bring these two communities closer. Agile Beeswax tried to integrate different methodologies and practices in the development process to obtain an integrated method. We combined some scrum management practices, software engineering practices, and operational practices into one methodology. To achieve our purpose, the work has been divided into five main phases: Phase 1: A systematic literature review approach to review existing mobile application development methods. Phase 2: Interviews with mobile application developers working in small to medium software companies. Phase 3: Survey to a group of 35 experts, including academics and developers, to extract valuable knowledge about mobile development. Phase 4: Proposal of a new methodology for mobile application development. Phase 5: Validation of the proposed methodology using a second group of 35 experts, including mobile application developers and academic communities (some of them participated in the first survey). Conclusion: We need an effective and practical methodology for mobile application development. An efficient development methodology may assist increase competitive advantage and decreasing release cycles, which is critical in the mobile application development process. The results in this thesis and the proposed methodology for developing mobile applications are intended to serve as support for mobile application developers.Las aplicaciones móviles han experimentado un gran desarrollo en los últimos años y, con este crecimiento, han evolucionado también las herramientas, los dispositivos y los métodos para desarrollar estas aplicaciones. Sin embargo, las metodologías de desarrollo de estas aplicaciones móviles no han experimentado el mismo crecimiento que su uso. La investigación en ingeniería de software sobre metodologías de desarrollo de aplicaciones móviles no ha avanzado al mismo ritmo que la adopción de aplicaciones móviles. Solo unas pocas metodologías de desarrollo de aplicaciones móviles se han presentado en la literatura científica, especialmente si nos centramos en metodologías ágiles específicas para desarrollo móvil. Además, los talleres de ideas y conceptos para crear la applicación, la recopilación de requisitos, el diseño de la interfaz de usuario y la experiencia del usuario, la implementación, el mantenimiento, la complejidad de las pruebas, el consumo de energía y las actividades de evaluación de proyectos de desarrollo móvil reciben poca atención en las metodologías existentes. Paralelamente, los métodos de desarrollo actuales no manejan suficientemente las limitaciones especiales que presetan las aplicaciones móviles, tales como facilitar las características necesarias para facilitar y soportar la participación de los usuarios en el proceso de desarrollo. Después, del exhaustivo estudio realizado en el mundo académico e industrial acerca del desarrollo de aplicaciones móviles, en nuestra opinión es indiscutible que la investigación en el proceso de desarrollo de aplicaciones móviles debe seguir creciendo. El desarrollo de aplicaciones móviles es un entorno altamente competitivo y, en nuestra opinión, las metodologías ágiles pueden permitir que los equipos generen valor más rápido, con mayor calidad y previsibilidad. El desarrollo de aplicaciones móviles tiene requisitos únicos y los métodos ágiles pueden abordar algunos de estos requisitos, como el cambio continuo en los requisitos de las aplicaciones móviles o la integración de los usuarios durante todo el proceso. Un proceso de desarrollo eficiente puede ayudar a aumentar la ventaja competitiva de los productos móviles y disminuir sus ciclos de lanzamiento. Por ello, nuestro objetivo es revisar las metodologías y modelos existentes para el desarrollo de aplicaciones móviles en la literatura científica y metodologías reales adoptadas por expertos en las comunidades de desarrollo ya que esto nos ayudará a identificar y dirigir las principales prácticas en el proceso de desarrollo de aplicaciones móviles. Basado en un marco previamente definido, se ha realizado un análisis de estos modelos y su utilidad para la industria para crear una nueva metodología para desarrollar aplicaciones móviles que se adapten a las comunidades académicas y de la industria. Este nuevo proceso metodológico basado en metodologías ágiles para el desarrollo de aplicaciones se ha denominado Agile Beeswax. Por lo tanto, Agile Beeswax se concibe después de identificar los problemas, desafíos y requisitos únicos del proceso de desarrollo móvil, y se define como un proceso de desarrollo iterativo e incremental integrado para desarrollar aplicaciones móviles. Una de sus principales fortalezas es que ha sido creado con perspectivas académicas y empresariales para acercar a estas dos comunidades. Además, Agile Beeswax ha intentado integrar diferentes metodologías y prácticas en el proceso de desarrollo para obtener un método integrado. Concretamente, combinamos algunas prácticas de gestión de scrum, prácticas de ingeniería de software y prácticas operativas en una sola metodología. Para lograr nuestro propósito, el estudio se ha dividido en cinco fases principales: Fase 1: Un enfoque de revisión sistemática de la literatura para revisar los métodos de desarrollo de aplicaciones móviles existentes. Fase 2: Entrevistas con desarrolladores de aplicaciones móviles que trabajan en pequeñas y medianas empresas de software. Fase 3: Encuesta a un grupo de 35 expertos, incluidos académicos y desarrolladores, para extraer conocimientos valiosos sobre el desarrollo móvil. Fase 4: Propuesta de una nueva metodología para el desarrollo de aplicaciones móviles. Fase 5: Validación de la metodología propuesta utilizando un segundo grupo de 35 expertos, entre desarrolladores de aplicaciones móviles y comunidades académicas (algunos de ellos participaron en la primera encuesta). Conclusión: Necesitamos una metodología efectiva y práctica para el desarrollo de aplicaciones móviles. Una metodología de desarrollo eficiente puede ayudar a aumentar la ventaja competitiva y disminuir los ciclos de lanzamiento, lo cual es fundamental en el proceso de desarrollo de aplicaciones móviles. Los resultados de esta tesis y la metodología propuesta para el desarrollo de aplicaciones móviles pretenden servir de apoyo a los desarrolladores de aplicaciones móviles.Tesis Univ. Granada

The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function

The flexible C-terminal hypervariable region distinguishes K-Ras4B, an important proto-oncogenic GTPase, from other Ras GTPases. This unique lysine-rich portion of the protein harbors sites for post-translational modification, including cysteine prenylation, carboxymethylation, phosphorylation, and likely many others. The functions of the hypervariable region are diverse, ranging from anchoring K-Ras4B at the plasma membrane to sampling potentially auto-inhibitory binding sites in its GTPase domain and participating in isoform-specific protein–protein interactions and signaling. Despite much research, there are still many questions about the hypervariable region of K-Ras4B. For example, mechanistic details of its interaction with plasma membrane lipids and with the GTPase domain require further clarification. The roles of the hypervariable region in K-Ras4B-specific protein–protein interactions and signaling are incompletely defined. It is also unclear why post-translational modifications frequently found in protein polylysine domains, such as acetylation, glycation, and carbamoylation, have not been observed in K-Ras4B. Expanding knowledge of the hypervariable region will likely drive the development of novel highly-efficient and selective inhibitors of K-Ras4B that are urgently needed by cancer patients

Conformational Plasticity in Histone Deacetylases as a Source of New Discoveries

Histone deacetylase 3 (HDAC3) is a promising epigenetic drug target for multiple therapeutic applications. Direct and specific interaction between HDAC3 and the silencing mediator for retinoid or thyroid-hormone receptors (SMRT) is essential for enzymatic activity. The conformational plasticity of this complex and the nature of interactions with HDAC inhibitors in solution are unknown. Using novel photoreactive HDAC probes – “nanorulers”, we determined the distance between the catalytic site of the full-length HDAC3 and SMRT-DAD in solution at physiologically relevant conditions and found it to be substantially different from that predicted by the X-ray model with a 379-428aa truncated HDAC3. Further experiments indicated that in solution this distance might change in response to chemical stimuli, while the enzymatic activity remained unaffected. These observations were further validated by Saturation Transfer Difference (STD) NMR experiments. We propose that the observed changes in the distance are an important part of the histone code that remains to be explored. Mapping direct interactions and distances between macromolecules with such “nanorulers” as a function of cellular events facilitates better understanding of basic biology and ways for its manipulation in cell and tissue specific manner

Agile Beeswax: Mobile App Development Process and Empirical Study in Real Environment

Mobile application development is a highly competitive environment; agile methodologies can enable teams to provide value faster, with higher quality and predictability, and a better attitude to deal with the continuous changes that will arise in the mobile context application (App), and the positive impact of that on sustainable development through continuous progress. App development is different from other types of software. For this reason, our objective is to present a new agile-based methodology for app development that we call Agile Beeswax. Agile Beeswax is conceived after identifying the mobile development process’s issues and challenges, and unique requirements. Agile Beeswax is an incremental, iterative development process composed of two main iterative loops (sprints), the incremental design loop and the incremental development loop, and one bridge connecting these two sprints. Agile Beeswax is structured in six phases, idea and strategy, user experience design, user interface design, design to development, handoff and technical decisions, development, and deployment and monitoring. One of its main strengths is that it has been created with academic and business perspectives to bring these two communities closer. To achieve this purpose, our research methodology comprises four main phases: Phase 1: Extensive literature review of mobile development methodologies, Phase 2: Interviews with mobile application developers working in small to medium software companies, Phase 3: Survey to extract valuable knowledge about mobile development (which was carefully designed based on the results of the first and the second phases), and Phase 4: Proposal of a new methodology for the agile development of mobile applications. With the aim of integrating both perspectives, the survey was answered by a sample of 35 experts, including academics and developers. Interesting results have been collected and discussed in this paper (on issues such as the development process, the tools used during this process, and the general issues and challenges they encountered), laying the foundations of the methodology Agile Beeswax proposed to develop mobile apps. Our results and the proposed methodology are intended to serve as support for mobile application developers

NMR resonance assignment and structure prediction of the C-terminal domain of the microtubule end-binding protein 3.

End-binding proteins (EBs) associate with the growing microtubule plus ends to regulate microtubule dynamics as well as the interaction with intracellular structures. EB3 contributes to pathological vascular leakage through interacting with the inositol 1,4,5-trisphosphate receptor 3 (IP3R3), a calcium channel located at the endoplasmic reticulum membrane. The C-terminal domain of EB3 (residues 200-281) is functionally important for this interaction because it contains the effector binding sites, a prerequisite for EB3 activity and specificity. Structural data for this domain is limited. Here, we report the backbone chemical shift assignments for the human EB3 C-terminal domain and computationally explore its EB3 conformations. Backbone assignments, along with computational models, will allow future investigation of EB3 structural dynamics, interactions with effectors, and will facilitate the development of novel EB3 inhibitors

Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3.

We observed in PRESTO-Tango β-arrestin recruitment assays that the α1-adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) receptor (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. We screened a panel of 14 α1/2- and β1/2/3-AR antagonists for CXCR4 and atypical chemokine receptor (ACKR)3 agonist activity in PRESTO-Tango assays against the cognate agonist CXCL12. We observed that multiple α1-AR antagonists activate CXCR4 (CXCL12 = prazosin = cyclazosin > doxazosin) and ACKR3 (CXCL12 = prazosin = cyclazosin > alfuzosin = doxazosin = phentolamine > terazosin = silodosin = tamsulosin). The two strongest CXCR4/ACKR3 activators, prazosin and cyclazosin, were selected for a more detailed evaluation. We found that the drugs dose-dependently activate both receptors in β-arrestin recruitment assays, stimulate ERK1/2 phosphorylation in HEK293 cells overexpressing each receptor, and that their effects on CXCR4 could be inhibited with AMD3100. Both α1-AR antagonists induced significant chemical shift changes in the 1H-13C-heteronuclear single quantum correlation spectrum of CXCR4 and ACKR3 in membranes, suggesting receptor binding. Furthermore, prazosin and cyclazosin induced internalization of endogenous CXCR4/ACKR3 in human vascular smooth muscle cells (hVSMC). While these drugs did not in induce chemotaxis in hVSMC, they inhibited CXCL12-induced chemotaxis with high efficacy and potency (IC50: prazosin-4.5 nM, cyclazosin 11.6 pM). Our findings reveal unexpected pharmacological properties of prazosin, cyclazosin, and likely other α1-AR antagonists. The results of the present study imply that prazosin and cyclazosin are biased or partial CXCR4/ACKR3 agonists, which function as potent CXCL12 antagonists. Our findings could provide a mechanistic basis for previously observed anti-cancer properties of α1-AR antagonists and support the concept that prazosin could be re-purposed for the treatment of disease processes in which CXCR4 and ACKR3 are thought to play significant pathophysiological roles, such as cancer metastases or various autoimmune pathologies