Tbx1 Regulates the BMP-Smad1 Pathway in a Transcription Independent Manner

Tbx1 is a T-box transcription factor implicated in DiGeorge syndrome. The molecular function of Tbx1 is unclear although it can transactivate reporters with T-box binding elements. We discovered that Tbx1 binds Smad1 and suppresses the Bmp4/Smad1 signaling. Tbx1 interferes with Smad1 to Smad4 binding, and a mutation of Tbx1 that abolishes transactivation, does not affect Smad1 binding nor does affect the ability to suppress Smad1 activity. In addition, a disease-associated mutation of TBX1 that does not prevent transactivation, prevents the TBX1-SMAD1 interaction. Expression of Tbx1 in transgenic mice generates phenotypes similar to those associated with loss of a Bmp receptor. One phenotype could be rescued by transgenic Smad1 expression. Our data indicate that Tbx1 interferes with Bmp/Smad1 signaling and provide strong evidence that a T-box transcription factor has functions unrelated to transactivation

Model Transformation as Conservative Theory-Transformation

This is the final version. Available on open access from the Journal of Object Technology via the DOI in this recordModel transformations play a central role in model-driven software development. Hence, logical unsafe model transformation can result in erroneous systems. Still, most model transformations are written in languages that do not provide built-in safeness guarantees. We present a new technique to construct tool support for domain-specific languages (DSLs) inside the interactive theorem prover environment Isabelle. Our approach is based on modeling the DSL formally in higher-order logic (HOL), modeling the API of Isabelle inside it, and defining the transformation between these two. Reflection via the powerful code generators yields code that can be integrated as extension into Isabelle and its user interface. Moreover, we use code generation to produce tactic code which is bound to appropriate command-level syntax. Our approach ensures the logical safeness (conservativity) of the theorem prover extension and, thus, provides a certified tool for the DSL in all aspects: the deductive capacities of theorem prover, code generation, and IDE support. We demonstrate our approach by extending Isabelle/HOL with support for UML/OCL and, more generally, providing support for a formal object-oriented modeling method

Recent Developments in OCL and Textual Modelling

The panel session of the 16th OCL workshop featured a lightning talk session for discussing recent developments and open questions in the area of OCL and textual modelling. During this session, the OCL community discussed, stimulated through short presentations by OCL experts, tool support, potential future extensions, and suggested initiatives to make the textual modelling community even more successful. This collaborative paper, to which each OCL expert contributed one section, summarises the discussions as well as describes the recent developments and open questions presented in the lightning talks

A Mouse Model of Hyperproliferative Human Epithelium Validated by Keratin Profiling Shows an Aberrant Cytoskeletal Response to Injury.

A validated animal model would assist with research on the immunological consequences of the chronic expression of stress keratins KRT6, KRT16, and KRT17, as observed in human pre-malignant hyperproliferative epithelium. Here we examine keratin gene expression profile in skin from mice expressing the E7 oncoprotein of HPV16 (K14E7) demonstrating persistently hyperproliferative epithelium, in nontransgenic mouse skin, and in hyperproliferative actinic keratosis lesions from human skin. We demonstrate that K14E7 mouse skin overexpresses stress keratins in a similar manner to human actinic keratoses, that overexpression is a consequence of epithelial hyperproliferation induced by E7, and that overexpression further increases in response to injury. As stress keratins modify local immunity and epithelial cell function and differentiation, the K14E7 mouse model should permit study of how continued overexpression of stress keratins impacts on epithelial tumor development and on local innate and adaptive immunity

A translation and preliminary validation of the Dutch Wound-QoL questionnaire

Background: Chronic wounds have a major impact on patients' health-related quality of life (HRQoL). Therefore, measuring HRQoL is an indispensable part of the treatment of patients with chronic wounds. The aim of this study was to translate and validate the Wound-QoL, a wound-specific HRQoL questionnaire, in a Dutch population. Methods: The Wound-QoL was translated into Dutch according to the international standards. Patients with chronic wounds were asked to complete questionnaires at baseline (T0) and after six weeks (T1), including Wound-QoL, EQ-5D-3L (a generic questionnaire to measure HRQoL) and a visual analogue scale (VAS) measuring wound pain. If patients were not able to complete the questionnaire by themselves, it was read out to them by a nurse. Further data were obtained from medical records. Results: Of the 120 patients included, 64 (53.3%) completed the questionnaire by themselves. To 55 patients (45.8%), the questionnaire was read out. The internal consistency of the Wound-QoL global score was high at both time points (T0: Cronbach's α = 0.89, T1: Cronbach's α = 0.92). The item selectivity for global score ranged from r = 0.25 to r = 0.77 at T0 and from r = 0.40 to r = 0.79 at T1. Overall, the self-completion and read-out subgroups showed similar internal consistency and item selectivity scores. With regard to convergent validity, significant correlations were found between Wound-QoL and EQ-5D-3L (T0: r = - 0.45, p < 0.001, T1: r = - 0.50, p < 0.001) as well as between Wound-QoL and pain VAS (T0: r = 0.23, p = 0.012, T1: r = 0.37, p = 0.001) at both time points. Responsiveness analyses showed significant correlations between changes in Wound-QoL and changes in EQ-5D-3L (r = - 0.37, p < 0.001), pain VAS (r = 0.24, p = 0.044) and wound size (r = 0.24, p = 0.013). The self-completion and read-out subgroups showed differences in convergent validity and responsiveness. Conclusions: The results indicate that the Dutch version of the Wound-QoL has positive psychometric properties. However, more research is needed to further explore the differences between self-completed and read-out questionnaires

Analysis and simulation of a mathematical model of tuberculosis transmission in Democratic Republic of the Congo

According to the World Health Organization reports, tuberculosis (TB) remains one of the top 10 deadly diseases of recent decades in the world. In this paper, we present the modeling, analysis and simulation of a mathematical model of TB transmission in a population incorporating several factors and study their impact on the disease dynamics. The spread of TB is modeled by eight compartments including different groups, which are too often not taken into account in the projections of tuberculosis incidence. The rigorous mathematical analysis of this model is provided, the basic reproduction number (R0) is obtained and used for TB dynamics control. The results obtained show that lost to follow-up and transferred individuals constitute a risk, but less than the cases carrying germs. Rapidly evolving latent/exposed cases are responsible for the incidence increasing in the short and medium term, while slower evolving latent/exposed cases will be responsible for the persistent long-term incidence and maintenance of TB and delay elimination in the population. The numerical simulations of the model show that, with certain parameters, TB will die out or sensibly reduce in the entire Democratic Republic of the Congo (DRC) population. The strategies on which the DRC’s health system is currently based to fight this disease show their weaknesses because the TB situation in the DRC remains endemic. But monitoring contact, detection of latent individuals and their treatment are actions to be taken to reduce the incidence of the disease and thus effectively control it in the population.Mathematical Science

Microprojection arrays applied to skin generate mechanical stress, induce an inflammatory transcriptome and cell death, and improve vaccine-induced immune responses

Abstract: Chemical adjuvants are typically used to improve immune responses induced by immunisation with protein antigens. Here we demonstrate an approach to enhance immune responses that does not require chemical adjuvants. We applied microprojection arrays to the skin, producing a range of controlled mechanical energy to invoke localised inflammation, while administering influenza split virus protein antigen. We used validated computational modelling methods to identify links between mechanical stress and energy generated within the skin strata and resultant cell death. We compared induced immune responses to those induced by needle-based intradermal antigen delivery and used a systems biology approach to examine the nature of the induced inflammatory response, and correlated this with markers of cell stress and death. Increasing the microprojection array application energy and the addition of QS-21 adjuvant were each associated with enhanced antibody response to delivered antigen and with induction of gene transcriptions associated with TNF and NF-κB signalling pathways. We concluded that microprojection intradermal antigen delivery inducing controlled local cell death could potentially replace chemical adjuvants to enhance the immune response to protein antigen

Formal Model-Based Assurance Cases in Isabelle/SACM : An Autonomous Underwater Vehicle Case Study

Isabelle/SACM is a tool for automated construction of model-based assurance cases with integrated formal methods, based on the Isabelle proof assistant. Assurance cases show how a system is safe to operate, through a human comprehensible argument demonstrating that the requirements are satisfied, using evidence of various provenances. They are usually required for certification of critical systems, often with evidence that originates from formal methods. Automating assurance cases increases rigour, and helps with maintenance and evolution. In this paper we apply Isabelle/SACM to a fragment of the assurance case for an autonomous underwater vehicle demonstrator. We encode the metric unit system (SI) in Isabelle, to allow modelling requirements and state spaces using physical units. We develop a behavioural model in the graphical RoboChart state machine language, embed the artifacts into Isabelle/SACM, and use it to demonstrate satisfaction of the requirements