There and back again: molecular phylogenetics of the Brazilian endemic Psyllocarpus (Rubiaceae: Spermacoceae) supports a circumscription of the genus based on its original concept

The Spermacoce clade (tribe Spermacoceae) is one of the most taxonomically complex groups in Rubiaceae due to the unclear delimitation of Borreria and Spermacoce, in which several smaller genera are phylogenetically intermingled. One of these genera is the Brazilian endemic Psyllocarpus, whose circumscription was broadened, thereby including two sections. Psyllocarpus sect. Psyllocarpus, being based on the original genus delineation, includes nine species, distributed in the Cerrado and campo rupestre of eastern Brazil, whereas P. sect. Amazonica comprises three species, occurring in the Amazonian campinas. Furthermore, P. intermedius was not classified in any of these sections when it was later described. In order to test the monophyly of Psyllocarpus and assess its relationships to other genera, we conducted phylogenetic analyses, sampling across the whole Spermacoce clade, including nearly all Psyllocarpus species. A combined nuclear ribosomal (ETS and ITS) and plastid (rps16 and trnLtrnF) dataset was generated, representing 124 species (ca 25% of the species in the clade) in 15 genera (ca 65%). Various methodologies were applied to investigate the degree of incongruence among markers and address the lack of resolution and low support values for some branches. Our results revealed that Psyllocarpus is not monophyletic. Psyllocarpus campinorum (from P . sect. Amazonica) and P intermedius are situated as distinct lineages in the Spermacoce clade, yet do not belong to Psyllocarpus. Members of section Psyllocarpus form a strongly supported clade sister to Staelia and was recovered with high to maximum support across different datasets and inference methods. Therefore, Psyllocarpus has to be circumscribed based on its original concept, excluding P. sect. Amazonica and P. intermedius. This establishes the genus as a monophyletic and easily diagnosable taxon, characterized by terete leaves, homostylous flowers, a bilobate calyx, included stamens and style, and compressed, septifragally dehiscent capsules with a persistent septum

Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation

Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master lipid regulator the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and its transcriptional targets both in cancer and lipogenic tissue. OGT regulates SREBP-1 protein expression via AMP-activated protein kinase (AMPK). SREBP-1 is critical for OGT-mediated regulation of cell survival and of lipid synthesis, as overexpression of SREBP-1 rescues lipogenic defects associated with OGT suppression, and tumor growth in vitro and in vivo. These results unravel a previously unidentified link between O-GlcNAcylation, lipid metabolism and the regulation of SREBP-1 in cancer and suggests a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate lipid metabolism

International consensus for ultrasound lesions in gout: Results of delphi process and web-reliability exercise

Objective. To produce consensus-based definitions of the US elementary lesions in gout and to test their reliability in a web-based exercise. Methods. The process consisted of two steps. In the first step a written Delphi questionnaire was developed from a systematic literature review and expert international consensus. This collated information resulted in four statements defining US elementary lesions: double contour (DC), tophus, aggregates and erosion. The Delphi questionnaire was sent to 35 rheumatology experts in US, asking them to rate their level of agreement or disagreement with each statement. The second step tested the reliability by a web-exercise. US images of both normal and gouty elementary lesions were collected by the participants. A facilitator then constructed an electronic database of 110 images. The database was sent to the participants, who evaluated the presence/absence of US elementary lesions. A group of 20 images was displayed twice to evaluate intra-reader reliability. Results. A total of 32 participants responded to the questionnaires. Good agreement (>80%) was obtained for US definitions on DC, tophus, aggregates and erosion in the Delphi exercise after three rounds. The reliability on images showed inter-reader κ values for DC, tophus, aggregates, erosion findings of 0.98, 0.71, 0.54 and 0.85, respectively. The mean intra-reader κ values were also acceptable: 0.93, 0.78, 0.65 and 0.78, respectively. Conclusion. This, the first consensus-based US definition of elementary lesions in gout, demonstrated good reliability overall. It constitutes an essential step in developing a core outcome measurement that permits a higher degree of homogeneity and comparability between multicentre studies

Determining Contingencies in the Management of Construction Projects

[EN] This research describes the managerial approaches that contractors follow to determine different types of contingencies in construction project management. Two large Spanish general contractors were selected for an in-depth analysis. Interviews and surveys were conducted with six additional companies to explore the external validity of the findings. Managers constrain time and cost buffers through project objectives, applying heuristics to determine inventory buffers. The management of capacity buffers is entrusted to subcontractors. The contractors take advantage of scope and quality buffers to meet project objectives but rarely share these buffers with the owner, unless the owner is an internal client.Ortiz-González, JI.; Pellicer, E.; Molenaar, KR. (2019). Determining Contingencies in the Management of Construction Projects. Project Management Journal. 50(2):226-242. https://doi.org/10.1177/8756972819827389S226242502Adafin, J., Wilkinson, S., Rotimi, J. O. B., & Odeyinka, H. (2014). Accuracy in Design Stage Cost Estimating through Risk-contingency Analysis: A Theoretical Exploration. Construction Research Congress 2014. doi:10.1061/9780784413517.151Ballard, G., & Howell, G. (1998). Shielding Production: Essential Step in Production Control. Journal of Construction Engineering and Management, 124(1), 11-17. doi:10.1061/(asce)0733-9364(1998)124:1(11)Barraza, G. A. (2011). Probabilistic Estimation and Allocation of Project Time Contingency. Journal of Construction Engineering and Management, 137(4), 259-265. doi:10.1061/(asce)co.1943-7862.0000280Blomquist, T., Hällgren, M., Nilsson, A., & Söderholm, A. (2010). Project-as-Practice: In Search of Project Management Research that Matters. Project Management Journal, 41(1), 5-16. doi:10.1002/pmj.20141Chan, E. H., & Au, M. C. (2009). Factors Influencing Building Contractors’ Pricing for Time-Related Risks in Tenders. Journal of Construction Engineering and Management, 135(3), 135-145. doi:10.1061/(asce)0733-9364(2009)135:3(135)De la Cruz, M. P., del Caño, A., & de la Cruz, E. (2006). Downside Risks in Construction Projects Developed by the Civil Service: The Case of Spain. Journal of Construction Engineering and Management, 132(8), 844-852. doi:10.1061/(asce)0733-9364(2006)132:8(844)Ford, D. N. (2002). Achieving Multiple Project Objectives through Contingency Management. Journal of Construction Engineering and Management, 128(1), 30-39. doi:10.1061/(asce)0733-9364(2002)128:1(30)González, V., Alarcón, L. F., & Molenaar, K. (2009). Multiobjective design of Work-In-Process buffer for scheduling repetitive building projects. Automation in Construction, 18(2), 95-108. doi:10.1016/j.autcon.2008.05.005Guest, G., Bunce, A., & Johnson, L. (2006). How Many Interviews Are Enough? Field Methods, 18(1), 59-82. doi:10.1177/1525822x05279903Günhan, S., & Arditi, D. (2007). Budgeting Owner’s Construction Contingency. Journal of Construction Engineering and Management, 133(7), 492-497. doi:10.1061/(asce)0733-9364(2007)133:7(492)Hällgren, M., & Wilson, T. L. (2008). The nature and management of crises in construction projects: Projects-as-practice observations. International Journal of Project Management, 26(8), 830-838. doi:10.1016/j.ijproman.2007.10.005Harbuck R. H. (2004). Competitive bidding for highway construction projects (pp. ES91–ES94). Morgantown, WV: AACE International Transactions.HORMAN, M., & KENLEY, R. (1998). Process Dynamics: Identifying a Strategy for the Deployment of Buffers in Building Projects. International Journal of Logistics Research and Applications, 1(3), 221-237. doi:10.1080/13675569808962049Horman, M. J., & Thomas, H. R. (2005). Role of Inventory Buffers in Construction Labor Performance. Journal of Construction Engineering and Management, 131(7), 834-843. doi:10.1061/(asce)0733-9364(2005)131:7(834)Howell, G., Laufer, A., & Ballard, G. (1993). Interaction between Subcycles: One Key to Improved Methods. Journal of Construction Engineering and Management, 119(4), 714-728. doi:10.1061/(asce)0733-9364(1993)119:4(714)Howell, G., Laufer, A., & Ballard, G. (1993). Uncertainty and project objectives. Project Appraisal, 8(1), 37-43. doi:10.1080/02688867.1993.9726884Idrus, A., Fadhil Nuruddin, M., & Rohman, M. A. (2011). Development of project cost contingency estimation model using risk analysis and fuzzy expert system. Expert Systems with Applications, 38(3), 1501-1508. doi:10.1016/j.eswa.2010.07.061Laryea, S., & Hughes, W. (2011). Risk and Price in the Bidding Process of Contractors. Journal of Construction Engineering and Management, 137(4), 248-258. doi:10.1061/(asce)co.1943-7862.0000293Leach, L. (2003). Schedule and Cost Buffer Sizing: How to Account for the Bias between Project Performance and Your Model. Project Management Journal, 34(2), 34-47. doi:10.1177/875697280303400205Lee, S., Peña-Mora, F., & Park, M. (2006). Reliability and Stability Buffering Approach: Focusing on the Issues of Errors and Changes in Concurrent Design and Construction Projects. Journal of Construction Engineering and Management, 132(5), 452-464. doi:10.1061/(asce)0733-9364(2006)132:5(452)Oviedo-Haito, R. J., Jiménez, J., Cardoso, F. F., & Pellicer, E. (2014). Survival Factors for Subcontractors in Economic Downturns. Journal of Construction Engineering and Management, 140(3), 04013056. doi:10.1061/(asce)co.1943-7862.0000811Pellicer, E., Sanz, M. A., Esmaeili, B., & Molenaar, K. R. (2016). Exploration of Team Integration in Spanish Multifamily Residential Building Construction. Journal of Management in Engineering, 32(5), 05016012. doi:10.1061/(asce)me.1943-5479.0000438Pellicer, E., & Victory, R. (2006). IMPLEMENTATION OF PROJECT MANAGEMENT PRINCIPLES IN SPANISH RESIDENTIAL DEVELOPMENTS. International Journal of Strategic Property Management, 10(4), 233-248. doi:10.3846/1648715x.2006.9637555Rooke, J., Seymour, D., & Fellows, R. (2004). Planning for claims: an ethnography of industry culture. Construction Management and Economics, 22(6), 655-662. doi:10.1080/014461904200026324Slauson N. P. (2005). The effectiveness of the construction contract (pp. PM121–PM127). Morgantown, WV: AACE International Transactions.Tah, J. H. M., Thorpe, A., & McCaffer, R. (1993). Contractor project risks contingency allocation using linguistic approximation. Computing Systems in Engineering, 4(2-3), 281-293. doi:10.1016/0956-0521(93)90052-xTaylor, J. E., Dossick, C. S., & Garvin, M. (2011). Meeting the Burden of Proof with Case-Study Research. Journal of Construction Engineering and Management, 137(4), 303-311. doi:10.1061/(asce)co.1943-7862.0000283Thal, A. E., Cook, J. J., & White, E. D. (2010). 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BH3-only proteins BIM and PUMA in the regulation of survival and neuronal differentiation of newly generated cells in the adult mouse hippocampus

Neurogenesis persists in the adult hippocampus, where several thousand neurons are born every day. Most of the newly generated cells are eliminated by apoptosis, possibly because of their failure to integrate properly into neural networks. The BH3-only proteins Bim and Puma have been shown to mediate trophic factor withdrawal- and anoikis-induced apoptosis in various systems. We therefore determined their impact on proliferation, survival, and differentiation of adult-generated cells in the mouse hippocampus using gene-deficient mice. Wild-type, bim-, and puma-deficient mice showed similar rates of precursor cell proliferation, as evidenced by 5-bromo-2-deoxyuridine (BrdU)-incorporation. Deficiency in either bim or puma significantly increased the survival of adult-born cells in the dentate gyrus (DG) after 7 days. Consistently, we detected increased numbers of doublecortin (DCX)-positive and fewer terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelled-positive cells in the DG of bim- and puma-deficient mice. Bim and puma deficiency did not change early markers of neuronal differentiation, as evidenced by BrdU/DCX double-labelling. However, BrdU/NeuN double-labelling revealed that deficiency of bim, but not puma, accelerated the differentiation of newly generated cells into a neuronal phenotype. Our data show that Bim and Puma are prominently involved in the regulation of neuronal progenitor cell survival in the adult DG, but also suggest that Bim has an additional role in neuronal differentiation of adult-born neural precursor cells

Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans.

BACKGROUND/OBJECTIVES: Obesity has been associated with both changes in adipose tissue lipid metabolism and inflammation. A key class of lipid-derived signalling molecules involved in inflammation are the prostaglandins. In this study, we aimed to determine how obesity affects the levels of prostaglandins within white adipose tissue (WAT) and determine which cells within adipose tissue produce them. To avoid the effects of cellular stress on prostaglandin levels, we developed a multivariate statistical approach in which metabolite concentrations and transcriptomic data were integrated, allowing the assignment of metabolites to cell types. SUBJECTS/METHODS: Eicosanoids were measured by liquid chromatography-tandem mass spectrometry and mRNA levels using real-time PCR. Eicosanoid levels and transcriptomic data were combined using principal component analysis and hierarchical clustering in order to associate metabolites with cell types. Samples were obtained from C57Bl/6 mice aged 16 weeks. We studied the ob/ob genetically obese mouse model and diet-induced obesity model. We extended our results in mice to a cohort of morbidly obese humans undergoing bariatric surgery. RESULTS: Using our modelling approach, we determined that prostglandin D₂ (PGD₂) in adipose tissue was predominantly produced in macrophages by the haematopoietic isoform of prostaglandin D synthase (H-Pgds). Analysis of sub-fractionated WAT confirmed that H-Pgds was expressed in adipose tissue macrophages (ATMs). Furthermore, H-Pgds expression in ATMs isolated from lean and obese mice was consistent with it affecting macrophage polarisation. Functionally, we demonstrated that H-PGDS-produced PGD₂ polarised macrophages toward an M2, anti-inflammatory state. In line with a potential anti-inflammatory role, we found that H-PGDS expression in ATMs was positively correlated with both peripheral insulin and adipose tissue insulin sensitivity in humans. CONCLUSIONS: In this study, we have developed a method to determine the cellular source of metabolites within an organ and used it to identify a new role for PGD₂ in the control of ATM polarisation.HQL-79 was a kind gift of Professor Yoshihiro Urade. Professor Vidal-Puig was funded by the BHF, MRC and BBSRC. Dr Virtue was funded by the BBSRC and the BHF. Dr Eiden, Dr Masoodi and Dr Griffin were funded by the MRC. Dr Mok was funded by the Wellcome Trust.This is the final published version. It first appeared at http://www.nature.com/ijo/journal/vaop/ncurrent/full/ijo201534a.htm

Linking Changes in Epithelial Morphogenesis to Cancer Mutations Using Computational Modeling

Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects