Ruimte voor werk. bouwrijpe bedrijventerreinen, economische ontwikkeling en ruimtelijke planning in Vlaanderen

Is there a shortage of new industrial sites in Flanders? This paper develops a method to evaluate the availability of industrial sites. The evaluation is based on the idea that a "strategic supply" should always be available in each sub-region in order to guarantee further economic development. The results indicate that the available area for industrial sites is clearly insufficient in large parts of Flanders. We also formulate several policy recommendations. The Flemish Govermnent has to take simultaneously structural and ad hoc measures. The structural measures should prevent that policy induced shortage of supply can pop up in the future. The ad hoc measures should speed up the supply in the next years.

Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.

The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity

Using metrics and sustainability considerations to evaluate the use of bio-based and non-renewable Brønsted acidic ionic liquids to catalyse Fischer esterification reactions

Background Ionic liquids have found uses in many applications, one of which is the joint solvation and catalysis of chemical transformations. Suitable Brønsted acidic ionic liquids can be formed by combining lactams with sulphonic acids. This work weighs up the relative benefits and disadvantages of applying these Brønsted acidic ionic liquid catalysts in esterifications through a series of comparisons using green chemistry metrics. Results A new bio-based ionic liquid was synthesised from N-methyl pyrrolidinone and p-cymenesulphonic acid, and tested as a catalyst in three Fischer esterifications under different conditions. An evaluation of the performance of this Brønsted acidic ionic liquid was made through the comparison to other ionic liquid catalysts as well as conventional homogeneous Brønsted acids. Conclusion Extending the argument to feedstock security as well as mass utilisation, ultimately in most instances traditional mineral acids appear to be the most sensible option for Brønsted acid esterification catalysts. Ester yields obtained from Brønsted acidic ionic liquid catalysed procedures were modest. This calls into question the diversity of research exploring esterification catalysis and the role of ionic liquids in esterifications

An efficient protocol for the global sensitivity analysis of stochastic ecological models

Stochastic simulation models requiring many input parameters are widely used to inform the management of ecological systems. The interpretation of complex models is aided by global sensitivity analysis, using simulations for distinct parameter sets sampled from multidimensional space. Ecologists typically analyze such output using an “emulator”; that is, a statistical model used to approximate the relationship between parameter inputs and simulation outputs and to derive sensitivity measures. However, it is typical for ad hoc decisions to be made regarding: (1) trading off the number of parameter samples against the number of simulation iterations run per sample, (2) determining whether parameter sampling is sufficient, and (3) selecting an appropriate emulator. To evaluate these choices, we coupled different sensitivity-analysis designs and emulators for a stochastic, 20-parameter model that simulated the re-introduction of a threatened species subject to predation and disease, and then validated the emulators against new output generated from the simulation model. Our results lead to the following sensitivity analysis-protocol for stochastic ecological models. (1) Run a single simulation iteration per parameter sample generated, even if the focal response is a probabilistic outcome, while sampling extensively across the parameter space. In contrast to designs that invested in many model iterations (tens to thousands) per parameter sample, this approach allowed emulators to capture the input-output relationship of the simulation model more accurately and also to produce sensitivity measures that were robust to variation inherent in the parameter-sampling stage. (2) Confirm that parameter sampling is sufficient, by emulating subsamples of the sensitivity-analysis output. As the subsample size is increased, the cross-validatory performance of the emulator and sensitivity measures derived from it should exhibit asymptotic behavior. This approach can also be used to compare candidate emulators and select an appropriate interaction depth. (3) If required, conduct further simulations for additional parameter samples, and then report sensitivity measures and illustrate key response curves using the selected emulator. This protocol will generate robust sensitivity measures and facilitate the interpretation of complex ecological models, while minimizing simulation effort.Thomas A. A. Prowse, Corey J. A. Bradshaw, Steven Delean, Phillip Cassey, Robert C. Lacy, Konstans Wells, Matthew E. Aiello-Lammens, H. R. Akçakaya, and Barry W. Broo

Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are aggressive hematological malignancies that are currently treated with high dose chemotherapy. Over the last years, the search towards novel and less toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell intrinsic properties of the tumor cell. However, non cell autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous IL7 can increase the expression of the oncogenic kinase PIM1 in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared to bulk non-treated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL PDX cells, ultimately resulting in non-cell autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7 responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

wallace 2: a shiny app for modeling species niches and distributions redesigned to facilitate expansion via module contributions

Released 4 years ago, the Wallace EcoMod application (R package wallace) provided an open-source and interactive platform for modeling species niches and distributions that served as a reproducible toolbox and educational resource. wallace harnesses R package tools documented in the literature and makes them available via a graphical user interface that runs analyses and returns code to document and reproduce them. Since its release, feedback from users and partners helped identify key areas for advancement, leading to the development of wallace 2. Following the vision of growth by community expansion, the core development team engaged with collaborators and undertook a major restructuring of the application to enable: simplified addition of custom modules to expand methodological options, analyses for multiple species in the same session, improved metadata features, new database connections, and saving/loading sessions. wallace 2 features nine new modules and added functionalities that facilitate data acquisition from climate-simulation, botanical and paleontological databases; custom data inputs; model metadata tracking; and citations for R packages used (to promote documentation and give credit to developers). Three of these modules compose a new component for environmental space analyses (e.g., niche overlap). This expansion was paired with outreach to the biogeography and biodiversity communities, including international presentations and workshops that take advantage of the software's extensive guidance text. Additionally, the advances extend accessibility with a cloud-computing implementation and include a suite of comprehensive unit tests. The features in wallace 2 greatly improve its expandability, breadth of analyses, and reproducibility options, including the use of emerging metadata standards. The new architecture serves as an example for other modular software, especially those developed using the rapidly proliferating R package shiny, by showcasing straightforward module ingestion and unit testing. Importantly, wallace 2 sets the stage for future expansions, including those enabling biodiversity estimation and threat assessments for conservation.journal articl

Current understanding and future research priorities in malignancy associated with inborn errors of immunity and DNA repair disorders : the perspective of an interdisciplinary working group

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world