CCR2⁺CD103⁻ intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells

The identification of intestinal macrophages (m phi s) and dendritic cells (DCs) is a matter of intense debate. Although CD103(+) mononuclear phagocytes (MPs) appear to be genuine DCs, the nature and origins of CD103(-) MPs remain controversial. We show here that intestinal CD103(-)CD11b(+) MPs can be separated clearly into DCs and m phi s based on phenotype, gene profile, and kinetics. CD64(-)CD103(-)CD11b(+) MPs are classical DCs, being derived from Flt3 ligand-dependent, DC-committed precursors, not Ly6C hi monocytes. Surprisingly, a significant proportion of these CD103(-)CD11b(+) DCs express CCR2 and there is a selective decrease in CD103(-)CD11b(+) DCs in mice lacking this chemokine receptor. CCR2(+)CD103(-) DCs are present in both the murine and human intestine, drive interleukin (IL)-17a production by Tcells in vitro, and show constitutive expression of IL-12/IL-23p40. These data highlight the heterogeneity of intestinal DCs and reveal a bona fide population of CCR2(+) DCs that is involved in priming mucosal T helper type 17 (Th17) responses

Congenital hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Congenital hepatic fibrosis is an uncommon cause of portal hypertension. Despite the presence of portal hypertension, hepatocellular and renal function are usually well preserved. Congenital hepatic fibrosis is included in the group of congenital diseases of fibropolycystic disorders. These include a broad spectrum of clinical diseases which are usually accompanied by hepatic involvement.</p> <p>Case presentation</p> <p>We report the case of a 27-year-old Iranian woman with congenital hepatic fibrosis leading to cirrhosis and subsequently hepatocellular carcinoma.</p> <p>Conclusion</p> <p>Advanced cirrhosis was diagnosed and our patient was scheduled for liver transplantation. During preparation for transplant, a hepatic mass was discovered which was found to be hepatocellular carcinoma. Radiofrequency ablation was performed and our patient was referred for transplantation.</p

Pseudomonas aeruginosa Adaptation to Lungs of Cystic Fibrosis Patients Leads to Lowered Resistance to Phage and Protist Enemies

Pathogenic life styles can lead to highly specialized interactions with host species, potentially resulting in fitness trade-offs in other ecological contexts. Here we studied how adaptation of the environmentally transmitted bacterial pathogen, Pseudomonas aeruginosa, to cystic fibrosis (CF) patients affects its survival in the presence of natural phage (14/1, ΦKZ, PNM and PT7) and protist (Tetrahymena thermophila and Acanthamoebae polyphaga) enemies. We found that most of the bacteria isolated from relatively recently intermittently colonised patients (1-25 months), were innately phage-resistant and highly toxic for protists. In contrast, bacteria isolated from long time chronically infected patients (2-23 years), were less efficient in both resisting phages and killing protists. Moreover, chronic isolates showed reduced killing of wax moth larvae (Galleria mellonella) probably due to weaker in vitro growth and protease expression. These results suggest that P. aeruginosa long-term adaptation to CF-lungs could trade off with its survival in aquatic environmental reservoirs in the presence of microbial enemies, while lowered virulence could reduce pathogen opportunities to infect insect vectors; factors that are both likely to result in poorer environmental transmission. From an applied perspective, phage therapy could be useful against chronic P. aeruginosa lung infections that are often characterized by multidrug resistance: chronic isolates were least resistant to phages and their poor growth will likely slow down the emergence of beneficial resistance mutations

Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways. Methods: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first-tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels. Results: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95$2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported. Conclusion: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions

Immune Response to Lactobacillus plantarum Expressing Borrelia burgdorferi OspA Is Modulated by the Lipid Modification of the Antigen

Over the past decade there has been increasing interest in the use of lactic acid bacteria as mucosal delivery vehicles for vaccine antigens, microbicides and therapeutics. We investigated the mechanism by which a mucosal vaccine based in recombinant lactic acid bacteria breaks the immunological tolerance of the gut in order to elicit a protective immune response.We analyzed how the lipid modification of OspA affects the localization of the antigen in our delivery vehicle using a number of biochemistry techniques. Furthermore, we examined how OspA-expressing L. plantarum breaks the oral tolerance of the gut by stimulating human intestinal epithelial cells, peripheral blood mononuclear cells and monocyte derived dendritic cells and measuring cytokine production. We show that the leader peptide of OspA targets the protein to the cell envelope of L. plantarum, and it is responsible for protein export across the membrane. Mutation of the lipidation site in OspA redirects protein localization within the cell envelope. Further, we show that lipidated-OspA-expressing L. plantarum does not induce secretion of the pro-inflammatory cytokine IL-8 by intestinal epithelial cells. In addition, it breaks oral tolerance of the gut via Th1/Th2 cell mediated immunity, as shown by the production of pro- and anti-inflammatory cytokines by human dendritic cells, and by the production of IgG2a and IgG1 antibodies, respectively.Lipid modification of OspA expressed in L. plantarum modulates the immune response to this antigen through a Th1/Th2 immune response

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

A conceptual framework for crop-based agri-food supply chain characterization under uncertainty

[EN] Crop-based Agri-food Supply Chains (AFSCs) are complex systems that face multiple sources of uncertainty that can cause a significant imbalance between supply and demand in terms of product varieties, quantities, qualities, customer requirements, times and prices, all of which greatly complicate their management. Poor management of these sources of uncertainty in these AFSCs can have negative impact on quality, safety, and sustainability by reducing the logistic efficiency and increasing the waste. Therefore, it becomes crucial to develop models in order to deal with the key sources of uncertainty. For this purpose, it is necessary to precisely understand and define the problem under study. Even, the characterisation process of this domains is also a difficult and time-consuming task, especially when the right directions and standards are not in place. In this chapter, a Conceptual Framework is proposed that systematically collects those aspects that are relevant for an adequate crop-based AFSC management under uncertainty.Authors of this publication acknowledge the contribution of the Project 691249, RUC-APS "Enhancing and implementing Knowledge based ICT solutions within high Risk and Uncertain Conditions for Agriculture Production Systems" (www.ruc-aps.eu), funded by the European Union under their funding scheme H2020-MSCA-RISE-2015Alemany Díaz, MDM.; Esteso, A.; Ortiz Bas, Á.; Hernández Hormazabal, JE.; Fernández, A.; Garrido, A.; Martin, J.... (2021). A conceptual framework for crop-based agri-food supply chain characterization under uncertainty. Studies in Systems, Decision and Control. 280:19-33. https://doi.org/10.1007/978-3-030-51047-3_2S1933280Taylor, D.H., Fearne, A.: Towards a framework for improvement in the management of demand in agri-food supply chains. Supply Chain Manage. 11, 379–384 (2006)Matopoulos, A., Vlachopoulou, M., Manthou, V., Manos, B.: A conceptual framework for supply chain collaboration: empirical evidence from the agri-food industry. Supply Chain Manage. 12, 177–186 (2007)Ahumada, O., Villalobos, J.R.: Application of planning models in the agri-food supply chain: a review. Eur. J. Oper. Res. 196, 1–20 (2009)Iakovou, E., Vlachos, D., Achillas, C., Anastasiadis, F.: A methodological framework for the design of green supply chains for the agrifood sector. Paper presented at the 2nd international conference on supply chains, Katerini, 5–7 Oct 2012Manzini, R., Accorsi, R.: The new conceptual framework for food supply chain assessment. J. Food Eng. 115, 251–263 (2013)Shukla, M., Jharkharia, S.: Agri-fresh produce supply chain management: a state-of-the-art literature review. Int. J. Oper. Prod. Manage. 33, 114–158 (2013)Lemma, Y., Kitaw, D., Gatew, G.: Loss in perishable food supply chain: an optimization approach literature review. Int. J. Sci. Eng. Res. 5, 302–311 (2014)Tsolakis, N.K., Keramydas, C.A., Toka, A.K., Aidonis, D.A., Iakovou, E.T.: Agrifood supply chain management: a comprehensive hierarchical decision-making framework and a critical taxonomy. Biosyst. Eng. 120, 47–64 (2014)Van der Vorst, J.G., Da Silva, C.A., Trienekens, J.H.: Agro-industrial Supply Chain Management: Concepts and Applications. FAO (2007)Hernandez, J., Mortimer, M., Patelli, E., Liu, S., Drummond, C., Kehr, E., Calabrese, N., Iannacone, R., Kacprzyk, J., Alemany, M.M.E., Gardner, D.: RUC-APS: enhancing and implementing knowledge based ICT solutions within high risk and uncertain conditions for agriculture production systems. In: 11th International Conference on Industrial Engineering and Industrial Management, Valencia, Spain (2017)Miles, M.B., Huberman, A.M.: Qualitative Data Analysis: An Expanded Sourcebook. Sage Publications, Thousand Oaks (1994)Alemany, M.M.E., Alarcón, F., Lario, F.C., Boj, J.J.: An application to support the temporal and spatial distributed decision-making process in supply chain collaborative planning. Comput. Ind. 62, 519–540 (2011)Teimoury, E., Nedaei, H., Ansari, S., Sabbaghi, M.: A multi-objective analysis for import quota policy making in a perishable fruit and vegetable supply chain: a system dynamics approach. Comput. Electron. Agric. 93, 37–45 (2013)Kusumastuti, R.D., van Donk, D.P., Teunter, R.: Crop-related harvesting and processing planning: a review. Int. J. Prod. Econ. 174, 76–92 (2016)Zhang, W., Wilhelm, W.E.: OR/MS decision support models for the specialty crops industry: a literature review. Ann. Oper. Res. 190, 131–148 (2011)Grillo, H., Alemany, M.M.E., Ortiz, A.: A review of mathematical models for supporting the order promising process under lack of homogeneity in product and other sources of uncertainty. Comput. Ind. Eng. 91, 239–261 (2016)Blanco, A.M., Masini, G., Petracci, N., Bandoni, J.A.: Operations management of a packaging plant in the fruit industry. J. Food Eng. 70, 299–307 (2005)Grillo, H., Alemany, M.M.E., Ortiz, A., Fuertes-Miquel, V.S.: Mathematical modelling of the order-promising process for fruit supply chains considering the perishability and subtypes of products. Appl. Math. Model. 49, 255–278 (2017)Verdouw, C.N., Beulens, A.J.M., Trienekens, J.H., Wolferta, J.: Process modelling in demand-driven supply chains: a reference model for the fruit industry. Comput. Electron. Agric. 73, 174–187 (2010)Amorim, P., Günther, H., Almada-Lobo, B.: Multi-objective integrated production and distribution planning of perishable products. Int. J. Prod. Econ. 138, 89–101 (2012)Nahmias, S.: Perishable inventory theory: a review. Oper. Res. 30, 680–708 (1982)Mowat, A., Collins, R.: Consumer behavior and fruit quality: supply chain management in an emerging industry. Supply Chain Manage. 5, 45–54 (2000)Kazaz, B., Webster, S.: The impact of yield-dependent trading costs on pricing and production planning under supply uncertainty. M&SOM Manuf. Serv. Oper. Manage. 13, 404–417 (2011)Van der Vorst, J.G.: Effective food supply chains: generating, modelling and evaluating supply chain scenarios (2000)Fuertes-Miquel, V.S., Cuenca, L., Boza, A., Guyon, C., Alemany, M.M.E.: Conceptual framework for the characterization of vegetable breton supply chain sustainability in an uncertain context. In: 12th International Conference on Industrial Engineering and Industrial Management, XXII Congreso de Ingeniería de Organización, Girona, Spain, 12–13 July 2018Kummu, M., de Moel, H., Porkka, M., Siebert, S., Varis, O., Ward, P.J.: Lost food, wasted resources: global food supply chain losses and their impacts on freshwater, cropland, and fertiliser use. Sci. Total Environ. 438, 477–489 (2012)Hoekstra, S., Romme, J.: Integral Logistic Structures: Developing Customer-Oriented Goods Flow. Industrial Press Inc., New York (1992)Borodin, V., Bourtembourg, J., Hnaien, F., Labadie, N.: Handling uncertainty in agricultural supply chain management: a state of the art. Eur. J. Oper. Res. 254, 348–359 (2016)Handayati, Y., Simatupang, T.M., Perdana, T.: Agri-food supply chain coordination: the state-of-the-art and recent developments. Logist. Res. 8, 1–15 (2015)Mintzberg, H.: The Structuring of Organisations. Prentice-Hall, Upper Saddle River (1979)Keuning, D.: Grondslagen Van Het Management. Stenfert Kroese, Houten (1995) (in Dutch)Esteso, A., Alemany, M.M.E., Ortiz, A.: Conceptual framework for designing agri-food supply chains under uncertainty by mathematical programming models. Int. J. Prod. Res. (2018)Backus, G.B.C., Eidman, V.R., Dijkhuizen, A.A.: Farm decision making under risk and uncertainty. Neth. J. Agr. Sci. 45, 307–328 (1997)Esteso, A., Alemany, M.M.E., Ortiz, A.: Conceptual framework for managing uncertainty in a collaborative agri-food supply chain context. In: IFIP Advances in Information and Communication Technology, vol. 506, pp. 715–724 (2017)Mundi, I., Alemany, M.M.E., Poler, R., Fuertes-Miquel, V.S.: Review of mathematical models for production planning under uncertainty due to lack of homogeneity: proposal of a conceptual model. Int. J. Prod. Res. (2019)Grillo, H., Alemany, M.M.E., Ortiz, A., De Baets, B.: Possibilistic compositions and state functions: application to the order promising process for perishables. Int. J. Prod. Res. (2019)Soto-Silva, W.E., Nadal-Roig, E., González-Araya, M.C., Pla-Aragones, L.M.: Operational research models applied to the fresh fruit supply chain. Eur. J. Oper. Res. 251, 345–355 (2016)Farahani, R.Z., Rezapour, S., Drezner, T., Fallah, S.: Competitive supply chain network design: an overview of classifications, models, solution techniques and applications. Omega 45, 92–118 (2014)Banasik, A., Bloemhof-Ruwaard, J.M., Kanellopoulos, A., Claassen, G.D.H., van der Vorst, J.G.: Multi-criteria decision making approaches for green supply chains: a review. Flex. Serv. Manuf. J. 1–31 (2016)Paam, P., Berretta, R., Heydar, M., Middleton, R.H., García-Flores, R., Juliano, P.: Planning models to optimize the agri-fresh food supply chain for loss minimization: a review. In: Reference Module in Food Science (2016)Soysal, M., Bloemhof-Ruwaard, J.M., Meuwissen, M.P., van der Vorst, J.G.: A review on quantitative models for sustainable food logistics management. Int. J. Food Syst. Dyn. 3, 136–155 (2012

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs