Muc2 Protects against Lethal Infectious Colitis by Disassociating Pathogenic and Commensal Bacteria from the Colonic Mucosa

Despite recent advances in our understanding of the pathogenesis of attaching and effacing (A/E) Escherichia coli infections, the mechanisms by which the host defends against these microbes are unclear. The goal of this study was to determine the role of goblet cell-derived Muc2, the major intestinal secretory mucin and primary component of the mucus layer, in host protection against A/E pathogens. To assess the role of Muc2 during A/E bacterial infections, we inoculated Muc2 deficient (Muc2−/−) mice with Citrobacter rodentium, a murine A/E pathogen related to diarrheagenic A/E E. coli. Unlike wildtype (WT) mice, infected Muc2−/− mice exhibited rapid weight loss and suffered up to 90% mortality. Stool plating demonstrated 10–100 fold greater C. rodentium burdens in Muc2−/− vs. WT mice, most of which were found to be loosely adherent to the colonic mucosa. Histology of Muc2−/− mice revealed ulceration in the colon amid focal bacterial microcolonies. Metabolic labeling of secreted mucins in the large intestine demonstrated that mucin secretion was markedly increased in WT mice during infection compared to uninfected controls, suggesting that the host uses increased mucin release to flush pathogens from the mucosal surface. Muc2 also impacted host-commensal interactions during infection, as FISH analysis revealed C. rodentium microcolonies contained numerous commensal microbes, which was not observed in WT mice. Orally administered FITC-Dextran and FISH staining showed significantly worsened intestinal barrier disruption in Muc2−/− vs. WT mice, with overt pathogen and commensal translocation into the Muc2−/− colonic mucosa. Interestingly, commensal depletion enhanced C. rodentium colonization of Muc2−/− mice, although colonic pathology was not significantly altered. In conclusion, Muc2 production is critical for host protection during A/E bacterial infections, by limiting overall pathogen and commensal numbers associated with the colonic mucosal surface. Such actions limit tissue damage and translocation of pathogenic and commensal bacteria across the epithelium

Rise and Fall of an Anti-MUC1 Specific Antibody

So far, human antibodies with good affinity and specificity for MUC1, a transmembrane protein overexpressed on breast cancers and ovarian carcinomas, and thus a promising target for therapy, were very difficult to generate.A human scFv antibody was isolated from an immune library derived from breast cancer patients immunised with MUC1. The anti-MUC1 scFv reacted with tumour cells in more than 80% of 228 tissue sections of mamma carcinoma samples, while showing very low reactivity with a large panel of non-tumour tissues. By mutagenesis and phage display, affinity of scFvs was increased up to 500fold to 5,7×10(-10) M. Half-life in serum was improved from below 1 day to more than 4 weeks and was correlated with the dimerisation tendency of the individual scFvs. The scFv bound to T47D and MCF-7 mammalian cancer cell lines were recloned into the scFv-Fc and IgG format resulting in decrease of affinity of one binder. The IgG variants with the highest affinity were tested in mouse xenograft models using MCF-7 and OVCAR tumour cells. However, the experiments showed no significant decrease in tumour growth or increase in the survival rates. To study the reasons for the failure of the xenograft experiments, ADCC was analysed in vitro using MCF-7 and OVCAR3 target cells, revealing a low ADCC, possibly due to internalisation, as detected for MCF-7 cells.Antibody phage display starting with immune libraries and followed by affinity maturation is a powerful strategy to generate high affinity human antibodies to difficult targets, in this case shown by the creation of a highly specific antibody with subnanomolar affinity to a very small epitope consisting of four amino acids. Despite these "best in class" binding parameters, the therapeutic success of this antibody was prevented by the target biology

Urbanization Forecasts, Effects on Land Use, Biodiversity, and Ecosystem Services

Several studies in recent years have forecasted global urban expansion and examined its potential impacts on biodiversity and ecosystem services. The amount of urban land near protected areas (PAs) is expected to increase, on average, by more than three times between 2000 and 2030 (from 450,000 km2 circa 2000) around the world. During the same time period, the urban land in biodiversity hotspots, areas with high concentrations of endemic species, will increase by about four times on average. China will likely become the nation with the most urban land within 50 km of its PAs by 2030. The largest proportional change, however, will likely be in Mid-Latitudinal Africa; its urban land near PAs will increase 20 ± 5 times by 2030. The largest urban expansion in biodiversity hotspots, an increase of over 100,000 km2, is forecasted to occur in South America. The forecasts of the amount and location of urban land expansion are subject to many uncertainties in their underlying drivers including urban population and economic growth. Nevertheless, the direct impacts of urban expansion on biodiversity and ecosystem services will likely be significant. The forecasts point to the need to reconcile urban development and biodiversity conservation strategies. Urbanization will also have impacts on food and food security. While the direct loss of cropland to urban expansion is of concern to the extent that high-yielding croplands are lost, the indirect impacts of urbanization due to dietary changes to more meat-based food products can also be substantial. Presently, regional and global studies that forecast impacts of future urban expansion on biodiversity and ecosystem services are in their infancy and more analyses are needed especially focusing on interactive effects of factors that drive urbanization. We conclude by highlighting the knowledge gaps on implications of future urbanization and suggest research directions that would help fill these gaps

Sustainability, lean, green and eco-efficiency symbioses

A literature review was conducted aiming at investigating the use of Sustainability, Lean, Green and eco-efficiency concepts, as well as meaningful combinations of those, on the field of Production and Operations Management. The study reports on the scientific papers published in all major journals in the field over the period 2001–2015. A set of 83 papers from 40 journals were selected for further analyzes, aiming at uncovering the existing level of awareness and use of the synergic and symbiotic relationship between Lean Manufacturing and Green Production. The findings show that a modest share of papers, about 30 %, explicitly recognize the Lean-Green joint approach. The same study testifies a clear growth pattern, which is patently reinforced in the last two and a half years, on the number of papers that behold a combined approach towards more efficient and cleaner production activities. The research has highlighted that the Lean-Green link does, in fact, exist and is gaining momentum, but requires further reinforcements from the scientific community, as well as from the companies, to deliver excelled and environmentally sound production systems.FCT Strategic Project PEst2015-2020, reference UID/CEC/00319/2013.info:eu-repo/semantics/publishedVersio

The lean-green BOPSE indicator to assess efficiency and sustainability

Over the years, companies have been progressing their management strategies and transforming their production systems to cope with the pressing environmental challenges and remain competitive, prosper and meet themarket demands. It is no longer enough to only satisfy the demand. The companies face a new transformation on the way of "doing things", being it the way performance and efficiency is improved, or its relationship with all the stakeholders. Lean manufacturing and eco-efficiency propose a setting for progressively reducingwastes and environmental impacts. Although Lean Production was not developed to directly tackle sustainability issues, its principles and practices convey benefits that could be put, unquestionably, under the umbrella of Green and resulting in synergies known as the Lean-Green link. This chapter aims to present the Business Overall Performance and Sustainability Effectiveness (BOPSE) indicator, which is intended to measure the companies' Lean-Green compliance. The BOPSE indicator is an integrated metric on companies' operational performance and sustainability conformity. This indicator exploits the Lean-Green production synergies and is operationalized through an indicator that aggregates and combines Lean production and Green production features. This indicator weaves a number of sustainability issues, spread over its three dimensions, with those encompassed by the Overall Equipment Effectiveness (OEE) indicator. Therefore, the BOPSE indicator intends to assess the effectiveness of the businesses grounded on operational performance and sustainability compliance, aiming at identifying both specific limitations and broader opportunities for the global improvement of the companies. Hence, the BOPSE indicator drives companies in their way to meet some of 17 sustainable development goals, namely the 8th-"Decent work and economic growth", and the 12th-"Responsible consumption and production" sustainable development goals.This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT—Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2013