LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome

Natural variation for LPS-induced lethal inflammation in mice is useful for identifying new genes that regulate sepsis, which could form the basis for novel therapies for systemic inflammation in humans. Here we report that LPS resistance of the inbred mouse strain SPRET/Ei, previously reported to depend on the glucocorticoid receptor (GR), maps to the distal region of the X-chromosome. The GR-inducible gene Tsc22d3, encoding the protein Gilz and located in the critical region on the X-chromosome, showed a higher expressed SPRET/Ei allele, regulated in cis. Higher Gilz levels were causally related to reduced inflammation, as shown with knockdown and overexpression studies in macrophages. Transient overexpression of Gilz by hydrodynamic plasmid injection confirmed that Gilz protects mice against endotoxemia Our data strongly suggest that Gilz is responsible for the LPS resistance of SPRET/Ei mice and that it could become a treatment option for sepsis

Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13(-/-) mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13(-/-) mice compared to MMP13(+/+) mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13(-/-) mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential

Efficacy and safety of dalbavancin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and other infections in a real-life setting: data from an Italian observational multicentric study (DALBITA study)

Objectives: We evaluated the efficacy and safety of dalbavancin in ABSSSI and ‘other sites’ infections’ (OTA). Methods: Observational study involving 11 Italian hospitals including patients that received ≥1 dose of dalbavancin in 2016–2019. The outcome was end-of-treatment efficacy and safety in ABSSSI and OTA in a real-life setting. Results: 206 patients enrolled (males 50%, median age 62 [IQR 50–76] years), 60.2% ABSSSI, 39.8% OTA. 69.7% ABSSSI vs 90.7% OTA (p = 0.003) and 46.3% ABSSSI vs 37.2% OTA (p = 0.786) received previous and concomitant antibiotics, respectively. 82.5% reached clinical cure. Eleven (5.4%) patients had non-serious adverse events (AE). OTA patients showed longer hospitalization (13.5 days, 5.5–22 vs 3, 0–11.7; p<0.0001) and received longer previous (18 days, 9–30 vs 11, 7–19; p = 0.007)/concomitant antibiotic treatments (21 days, 14–52 vs 11, 8–14; p < 0.0001), compared to ABSSSI. ABSSSI and OTA showed similar efficacy (85.5% vs 75%, p = 0.459) and safety (no AE: 81.5% vs 64.3%, p = 0.258); efficacy was independent of previous/concomitant therapies. Conclusions: Dalbavancin demonstrated a success rate of >80%, with similar efficacy/safety in ABSSSI and off-label indications. The preferential use of dalbavancin as second-line or combination therapy would seem to suggest the need for in-depth studies focused on its off-label use

MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition

The nucleotide-binding-domain (NBD)-and leucine-rich repeat (LRR)-containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome drives pathological inflammation in a suite of autoimmune, metabolic, malignant, and neurodegenerative diseases. Additionally, NLRP3 gain-of-function point mutations cause systemic periodic fever syndromes that are collectively known as cryopyrin-associated periodic syndrome (CAPS). There is significant interest in the discovery and development of diarylsulfonylurea Cytokine Release Inhibitory Drugs (CRIDs) such as MCC950/CRID3, a potent and selective inhibitor of the NLRP3 inflammasome pathway, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight into the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome pathway. Here, we show that the NAIP, CIITA, HET-E, and TP1 (NACHT) domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labeling (PAL) of the NACHT domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance with this finding, MCC950/CRID3 failed to inhibit NLRP3-driven inflammatory pathology in two mouse models of CAPS. Moreover, it abolished circulating levels of interleukin (IL)-1 beta and IL-18 in lipopolysaccharide (LPS)-challenged wild-type mice but not in Nlrp3(L351P) knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wild-type NLRP3 as the molecular target of MCC950/CRID3 and show that CAPS-related NLRP3 mutants escape efficient MCC950/CRID3 inhibition. Collectively, this work suggests that MCC950/CRID3-based therapies may effectively treat inflammation driven by wild-type NLRP3 but not CAPS-associated mutants

NF-κB2 signalling in enteroids modulates enterocyte responses to secreted factors from bone marrow-derived dendritic cells

Alternative pathway NF-κB signalling regulates susceptibility towards developing inflammatory bowel disease (IBD), colitis-associated cancer and sepsis-associated intestinal epithelial cell apoptosis and shedding. However, the cell populations responsible for the perturbed alternative pathway NF-κB signalling in intestinal mucosal pathology remain unclear. In order to investigate the contribution of the epithelial compartment, we have tested whether NF-κB2 regulated transcription in intestinal epithelial cells controls the intestinal epithelial response to cytokines that are known to disrupt intestinal barrier permeability. Enteroids were generated from the proximal, middle and distal regions of small intestine (SI) from C57BL/6J wild-type mice and displayed region-specific morphology that was maintained during sub-culture. Enteroids treated with 100 ng/mL TNF were compared with corresponding regions of SI from C57BL/6J mice treated systemically with 0.33 mg/kg TNF for 1.5 h. TNF-induced apoptosis in all regions of the intestine in vitro and in vivo but resulted in Paneth cell degranulation only in proximal tissue-derived SI and enteroids. TNF also resulted in increased enteroid sphericity (quantified as circularity from two-dimensional bright field images). This response was dose and time-dependent and correlated with active caspase-3 immunopositivity. Proximal tissue-derived enteroids generated from Nfκb2−/− mice showed a significantly blunted circularity response following the addition of TNF, IFNγ, lipopolysaccharide (LPS) activated C57BL/6J-derived bone marrow-derived dendritic cells (BMDC) and secreted factors from LPS-activated BMDCs. However, Nfκb1−/− mouse-derived enteroids showed no significant changes in response to these stimuli. In conclusion, the selection of SI region is important when designing enteroid studies as region-specific identity and response to stimuli such as TNF are maintained in culture. Intestinal epithelial cells are at least partially responsible for regulating their own fate by modulating NF-κB2 signalling in response to stimuli known to be involved in multiple intestinal and systemic diseases. Future studies are warranted to investigate the therapeutic potential of intestinal epithelial NF-κB2 inhibition

TNFR1 inhibition with a nanobody protects against EAE development in mice

TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reported the generation of a Nanobody-based selective inhibitor of human TNFR1, TROS that will be tested in experimental autoimmune encephalomyelitis (EAE). We specifically antagonized TNF/TNFR1 signaling using TROS in a murine model of MS, namely MOG(35-55)-induced EAE. Because TROS does not cross-react with mouse TNFR1, we generated mice expressing human TNFR1 in a mouse TNFR1-knockout background (hTNFR1 Tg), and we determined biodistribution of Tc-99m-TROS and effectiveness of TROS in EAE in those mice. Biodistribution analysis demonstrated that intraperitoneally injected TROS is retained more in organs of hTNFR1 Tg mice compared to wild type mice. TROS was also detected in the cerebrospinal fluid (CSF) of hTNFR1 Tg mice. Prophylactic TROS administration significantly delayed disease onset and ameliorated its symptoms. Moreover, treatment initiated early after disease onset prevented further disease development. TROS reduced spinal cord inflammation and neuroinflammation, and preserved myelin and neurons. Collectively, our data illustrate that TNFR1 is a promising therapeutic target in MS

Drivers of Innovation Using BIM in Architecture, Engineering, and Construction Firms

This material may be downloaded for personal use only. Any other use requires prior permission of the American Society of Civil Engineers. This material may be found at https://doi.org/10.1061/9780784482889.023[Otros] Architecture, engineering, and construction (AEC) firms need to innovate in order to increase their business¿ competitiveness. Many companies around the world are considering the possibility of implementing building information modelling (BIM) in their projects without knowing its actual benefits for the business. The current literature recognizes certain barriers to BIM implementation; therefore, considering these barriers, this work proposes a holistic model that allows managers to explain how BIM can play an important role for the success of the AEC companies. The pillars of the model are a collaborative culture and training of employees in order to break down technological barriers. This way, BIM can help AEC companies to innovate. This proposal takes into consideration the three phases of the infrastructure life-cycle. In the design phase, the model considers 3D shape, scheduling (4D), costs (5D), and sustainability (6D). In the construction phase, the model focuses on supply chain and quality management. During the operation phase, the model is related to the virtual management of maintenance activities. Drivers of innovation should consider several facets: marketing, technology, organization, processes, and products. This model aims to enlighten the positive effects of a good strategic management using BIM on innovation activities in each of the phases of the infrastructure life-cycleVillena, F.; García-Segura, T.; Pellicer, E. (2020). Drivers of Innovation Using BIM in Architecture, Engineering, and Construction Firms. American Society of Civil Engineers. 210-222. https://doi.org/10.1061/9780784482889.023S210222Aibinu, A., & Venkatesh, S. (2014). Status of BIM Adoption and the BIM Experience of Cost Consultants in Australia. Journal of Professional Issues in Engineering Education and Practice, 140(3), 04013021. doi:10.1061/(asce)ei.1943-5541.0000193Alshubbak, A., Pellicer, E., Catalá, J., & Teixeira, J. M. C. (2015). A MODEL FOR IDENTIFYING OWNER’S NEEDS IN THE BUILDING LIFE CYCLE. Journal of Civil Engineering and Management, 21(8), 1046-1060. doi:10.3846/13923730.2015.1027257Autodesk Inc. (2012). Building information modelling [online] [8-06-2012]. Available from Internet: http://usa.autodesk.comAzhar, S., Khalfan, M., & Maqsood, T. (2015). Building information modelling (BIM): now and beyond. Construction Economics and Building, 12(4), 15-28. doi:10.5130/ajceb.v12i4.3032Blayse, A. M., & Manley, K. (2004). Key influences on construction innovation. Construction Innovation, 4(3), 143-154. doi:10.1108/14714170410815060Boland, R. J., Lyytinen, K., & Yoo, Y. (2007). Wakes of Innovation in Project Networks: The Case of Digital 3-D Representations in Architecture, Engineering, and Construction. Organization Science, 18(4), 631-647. doi:10.1287/orsc.1070.0304Bryde, D., Broquetas, M., & Volm, J. M. (2013). The project benefits of Building Information Modelling (BIM). International Journal of Project Management, 31(7), 971-980. doi:10.1016/j.ijproman.2012.12.001Chen, Y.-S. (2007). The Driver of Green Innovation and Green Image – Green Core Competence. Journal of Business Ethics, 81(3), 531-543. doi:10.1007/s10551-007-9522-1Cheng, Y.-M. (2018). Building Information Modeling for Quality Management. Proceedings of the 20th International Conference on Enterprise Information Systems. doi:10.5220/0006796703510358Chesbrough, H., & Crowther, A. K. (2006). Beyond high tech: early adopters of open innovation in other industries. R and D Management, 36(3), 229-236. doi:10.1111/j.1467-9310.2006.00428.xDavies, R., & Harty, C. (2013). Implementing ‘Site BIM’: A case study of ICT innovation on a large hospital project. Automation in Construction, 30, 15-24. doi:10.1016/j.autcon.2012.11.024Du Plessis, M. (2007). The role of knowledge management in innovation. Journal of Knowledge Management, 11(4), 20-29. doi:10.1108/13673270710762684Eastman, C., Teicholz, P., Sacks, R., & Liston, K. (2008). BIM Handbook. doi:10.1002/9780470261309Elmualim, A., & Gilder, J. (2013). BIM: innovation in design management, influence and challenges of implementation. Architectural Engineering and Design Management, 10(3-4), 183-199. doi:10.1080/17452007.2013.821399Erdogan, B., Anumba, C. J., Bouchlaghem, D., & Nielsen, Y. (2008). Collaboration Environments for Construction: Implementation Case Studies. Journal of Management in Engineering, 24(4), 234-244. doi:10.1061/(asce)0742-597x(2008)24:4(234)Fox, S., & Hietanen, J. (2007). Interorganizational use of building information models: potential for automational, informational and transformational effects. Construction Management and Economics, 25(3), 289-296. doi:10.1080/01446190600892995Franco, J., Mahdi, F., & Abaza, H. (2015). Using Building Information Modeling (BIM) for Estimating and Scheduling, Adoption Barriers. Universal Journal of Management, 3(9), 376-384. doi:10.13189/ujm.2015.030905Hameed, M. A., Counsell, S., & Swift, S. (2012). A conceptual model for the process of IT innovation adoption in organizations. Journal of Engineering and Technology Management, 29(3), 358-390. doi:10.1016/j.jengtecman.2012.03.007Harness S. H. (2008). 2008 documents AIA advance the use of BIM and integrated project delivery [online] [5 Diciembre 2008]. Available from Internet: http://www.aia.orgHobday, M. (2005). Firm-level Innovation Models: Perspectives on Research in Developed and Developing Countries. Technology Analysis & Strategic Management, 17(2), 121-146. doi:10.1080/09537320500088666Hong Y. Hammad A. Sepasgozar S. and Akbarnezhad A. (2019). "BIM adoption model for small and medium construction organizations in Australia" Engineering Construction and Architectural Management 26(2) 154-183. https://doi.org/10.1108/ECAM-04-2017-006410.1108/ECAM-04-2017-0064Hurley, R. F., & Hult, G. T. M. (1998). Innovation, Market Orientation, and Organizational Learning: An Integration and Empirical Examination. Journal of Marketing, 62(3), 42-54. doi:10.1177/002224299806200303Khosrowshahi, F., & Arayici, Y. (2012). Roadmap for implementation of BIM in the UK construction industry. Engineering, Construction and Architectural Management, 19(6), 610-635. doi:10.1108/09699981211277531Kleinschmidt, E. J., de Brentani, U., & Salomo, S. (2007). Performance of Global New Product Development Programs: A Resource-Based View. Journal of Product Innovation Management, 24(5), 419-441. doi:10.1111/j.1540-5885.2007.00261.xLee, S., Yu, J., & Jeong, D. (2015). BIM Acceptance Model in Construction Organizations. Journal of Management in Engineering, 31(3), 04014048. doi:10.1061/(asce)me.1943-5479.0000252Lu, Q., & Lee, S. (2017). Image-Based Technologies for Constructing As-Is Building Information Models for Existing Buildings. Journal of Computing in Civil Engineering, 31(4), 04017005. doi:10.1061/(asce)cp.1943-5487.0000652Miettinen, R., & Paavola, S. (2014). Beyond the BIM utopia: Approaches to the development and implementation of building information modeling. Automation in Construction, 43, 84-91. doi:10.1016/j.autcon.2014.03.009Motamedi, A., Hammad, A., & Asen, Y. (2014). Knowledge-assisted BIM-based visual analytics for failure root cause detection in facilities management. Automation in Construction, 43, 73-83. doi:10.1016/j.autcon.2014.03.012Oduyemi O Okoroh MI Fajana OS. (2017). "The application and barriers of BIM in sustainable building design" Journal of Facilities Management 15(1):15−34. https://doi.org/10.1108/JFM-03-2016-0008.10.1108/JFM-03-2016-0008Olawumi, T. O., Chan, D. W. M., Wong, J. K. W., & Chan, A. P. C. (2018). Barriers to the integration of BIM and sustainability practices in construction projects: A Delphi survey of international experts. Journal of Building Engineering, 20, 60-71. doi:10.1016/j.jobe.2018.06.017Ozorhon, B., & Oral, K. (2017). Drivers of Innovation in Construction Projects. Journal of Construction Engineering and Management, 143(4), 04016118. doi:10.1061/(asce)co.1943-7862.0001234Papadonikolaki, E. (2018). Loosely Coupled Systems of Innovation: Aligning BIM Adoption with Implementation in Dutch Construction. Journal of Management in Engineering, 34(6), 05018009. doi:10.1061/(asce)me.1943-5479.0000644Pellicer, E., Yepes, V., Correa, C. L., & Alarcón, L. F. (2014). Model for Systematic Innovation in Construction Companies. Journal of Construction Engineering and Management, 140(4). doi:10.1061/(asce)co.1943-7862.0000700Poirier, E., Forgues, D., & Staub-French, S. (2016). Collaboration through innovation: implications for expertise in the AEC sector. Construction Management and Economics, 34(11), 769-789. doi:10.1080/01446193.2016.1206660Poirier, E., Staub-French, S., & Forgues, D. (2015). Embedded contexts of innovation. Construction Innovation, 15(1), 42-65. doi:10.1108/ci-01-2014-0013Rowlinson S. Collins R. Tuuli M. and Jia A. (2010). Implementation of Building Information Modeling (BIM) in Construction: A Comparative Case Study. AIP Conference Proceedings. 1233. 572-577. 10.1063/1.3452236.Selçuk Çıdık, M., Boyd, D., & Thurairajah, N. (2017). Innovative Capability of Building Information Modeling in Construction Design. Journal of Construction Engineering and Management, 143(8), 04017047. doi:10.1061/(asce)co.1943-7862.0001337Stock, R. M., Six, B., & Zacharias, N. A. (2012). Linking multiple layers of innovation-oriented corporate culture, product program innovativeness, and business performance: a contingency approach. Journal of the Academy of Marketing Science, 41(3), 283-299. doi:10.1007/s11747-012-0306-5Succar, B., & Kassem, M. (2015). Macro-BIM adoption: Conceptual structures. Automation in Construction, 57, 64-79. doi:10.1016/j.autcon.2015.04.018Succar, B. (2009). Building information modelling framework: A research and delivery foundation for industry stakeholders. Automation in Construction, 18(3), 357-375. doi:10.1016/j.autcon.2008.10.003Taylor, J. E., & Bernstein, P. G. (2009). Paradigm Trajectories of Building Information Modeling Practice in Project Networks. Journal of Management in Engineering, 25(2), 69-76. doi:10.1061/(asce)0742-597x(2009)25:2(69)Tekla Corporation. (2013). Basic concepts [online] [ 16 Enero 2013]. Available from Internet: http://www.tekla.comVillena Manzanares, F., & Galiano Coronil, A. (2017). EL DESARROLLO URBANO SOSTENIBLE Y SUS IMPLICACIONES PARA LAS EMPRESAS Y LOS TERRITORIOS. Revista de Estudios Empresariales. Segunda Época, (1). doi:10.17561/ree.v0i1.3185Volk, R., Stengel, J., & Schultmann, F. (2014). Building Information Modeling (BIM) for existing buildings — Literature review and future needs. Automation in Construction, 38, 109-127. doi:10.1016/j.autcon.2013.10.023Whyte, J., Bouchlaghem, N., Thorpe, A., & McCaffer, R. (2000). From CAD to virtual reality: modelling approaches, data exchange and interactive 3D building design tools. Automation in Construction, 10(1), 43-55. doi:10.1016/s0926-5805(99)00012-6Wischnevsky, J. D., Damanpour, F., & Méndez, F. A. (2011). Influence of Environmental Factors and Prior Changes on the Organizational Adoption of Changes in Products and in Technological and Administrative Processes. British Journal of Management, 22(1), 132-149. doi:10.1111/j.1467-8551.2010.00700.xWong, K., & Fan, Q. (2013). Building information modelling (BIM) for sustainable building design. Facilities, 31(3/4), 138-157. doi:10.1108/02632771311299412Yepes, V., Pellicer, E., Alarcón, L. F., & Correa, C. L. (2016). Creative Innovation in Spanish Construction Firms. Journal of Professional Issues in Engineering Education and Practice, 142(1), 04015006. doi:10.1061/(asce)ei.1943-5541.0000251Yusof N. Seng Lai K and Mustafa Kamal E. (2017). "Characteristics of innovation orientations in construction companies" Journal of Engineering Design and Technology 15(4) 436-455. https://doi.org/10.1108/JEDT-06-2016-003710.1108/JEDT-06-2016-0037Zhou, Y., Yang, Y., & Yang, J.-B. (2019). Barriers to BIM implementation strategies in China. Engineering, Construction and Architectural Management, 26(3), 554-574. doi:10.1108/ecam-04-2018-015

Elevated apoptosis impairs epithelial cell turnover and shortens villi in TNF-driven intestinal inflammation

The intestinal epithelial monolayer, at the boundary between microbes and the host immune system, plays an important role in the development of inflammatory bowel disease (IBD), particularly as a target and producer of pro-inflammatory TNF. Chronic overexpression of TNF leads to IBD-like pathology over time, but the mechanisms driving early pathogenesis events are not clear. We studied the epithelial response to inflammation by combining mathematical models with in vivo experimental models resembling acute and chronic TNF-mediated injury. We found significant villus atrophy with increased epithelial cell death along the crypt-villus axis, most dramatically at the villus tips, in both acute and chronic inflammation. In the acute model, we observed overexpression of TNF receptor I in the villus tip rapidly after TNF injection and concurrent with elevated levels of intracellular TNF and rapid shedding at the tip. In the chronic model, sustained villus atrophy was accompanied by a reduction in absolute epithelial cell turnover. Mathematical modelling demonstrated that increased cell apoptosis on the villus body explains the reduction in epithelial cell turnover along the crypt-villus axis observed in chronic inflammation. Cell destruction in the villus was not accompanied by changes in proliferative cell number or division rate within the crypt. Epithelial morphology and immunological changes in the chronic setting suggest a repair response to cell damage although the villus length is not recovered. A better understanding of how this state is further destabilised and results in clinical pathology resembling IBD will help identify suitable pathways for therapeutic intervention