Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

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The trophic importance of epiphytic algae in a freshwater macrophyte system (Potamogeton perfoliatus L.): stable isotope and fatty acid analyses

Stable isotope and fatty acid analyses were used to study carbon sources for animals in a submerged plant bed. Epiphytes growing on Potamogeton perfoliatus, sand microflora, and alder leaves were the most important carbon sources. The most abundant macrophyte, P. perfoliatus was unimportant as a food source. Modelling (IsoSource) showed that epiphytes were the most important food source for the most abundant benthic invertebrates, the isopod Asellus aquaticus (annual mean contribution 64%), the amphipod Gammarus pulex (66%), and the gastropod Potamopyrgus antipodarum (83%). The mean annual contributions of sand microflora were, respectively, 21, 19, and 9%; and of alder leaves, 15, 15, and 8% for these three species. The relative importance of carbon sources varied seasonally. The relative contribution of epiphytes was lowest for all three grazer species in July: A. aquaticus 38%, G. pulex 43%, and P. antipodarum 42%. A decline in epiphyte biomass in summer may have caused this switch to less attractive food sources. P. perfoliatus provided habitat and shelter for consumers, but food was mainly supplied indirectly by providing space for attached epiphytes, which are fast-growing and provide a highly nutritious food source

The undebated issue of justice: silent discourses in Dutch flood risk management

Flood risk for all types of flooding is projected to increase based on climate change projections and increases in damage potential. These challenges are likely to aggravate issues of justice in flood risk management (henceforth FRM). Based on a discursive-institutionalist perspective, this paper explores justice in Dutch FRM: how do institutions allocate the responsibilities and costs for FRM for different types of flooding? What are the underlying conceptions of justice? What are the future challenges with regard to climate change? The research revealed that a dichotomy is visible in the Dutch approach to FRM: despite an abundance of rules, regulations and resources spent, flood risk or its management, are only marginally discussed in terms of justice. Despite that the current institutional arrangement has material outcomes that treat particular groups of citizens differently, depending on the type of flooding they are prone to, area they live in (unembanked/embanked) or category of user (e.g. household, industry, farmer). The paper argues that the debate on justice will (re)emerge, since the differences in distributional outcomes are likely to become increasingly uneven as a result of increasing flood risk. The Netherlands should be prepared for this debate by generating the relevant facts and figures. An inclusive debate on the distribution of burdens of FRM could contribute to more effective and legitimate FRM

The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis

The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches

Fungal vaccines and immunotherapeutics: current concepts and future challenges

Purpose of review The remarkable advances in modern medicine have paradoxically resulted in a rapidly expanding population of immunocompromised patients displaying extreme susceptibility to life-threatening fungal infections. There are currently no licensed vaccines, and the prophylaxis and therapy of fungal infections in at-risk individuals remains challenging, contributing to undesirable mortality and morbidity rates. The design of successful antifungal preventive approaches has been hampered by an insufficient understanding of the dynamics of the host-fungus interaction and the mechanisms that underlie heterogenous immune responses to vaccines and immunotherapy. Recent findings Recent advances in proteomics and glycomics have contributed to the identification of candidate antigens for use in subunit vaccines, novel adjuvants, and delivery systems to boost the efficacy of protective vaccination responses that are becoming available, and several targets are being exploited in immunotherapeutic approaches. Summary We review some of the emerging concepts as well as the inherent challenges to the development of fungal vaccines and immunotherapies to protect at-risk individuals.ThisworkwassupportedbytheNorthernPortugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundação para a Ciência e Tecnologia (FCT) (contracts IF/00735/ 2014 to A.C., and SFRH/BPD/96176/2013 to C.C).info:eu-repo/semantics/publishedVersio

Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects.

BACKGROUND: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. METHODS: We investigated in vitro and in vivo effects of metformin in humans. RESULTS: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production. CONCLUSION: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis

Reducing relative termination to dependency pair problems

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-21401-6_11Relative termination, a generalized notion of termination, has been used in a number of different contexts like proving the confluence of rewrite systems or analyzing the termination of narrowing. In this paper, we introduce a new technique to prove relative termination by reducing it to dependency pair problems. To the best of our knowledge, this is the first significant contribution to Problem #106 of the RTA List of Open Problems. The practical significance of our method is illustrated by means of an experimental evaluation.Germán Vidal is partially supported by the EU (FEDER) and the Spanish Ministerio de Economía y Competitividad under grant TIN2013-44742-C4-R and by the Generalitat Valenciana under grant PROMETEOII201/013. Akihisa Yamadais supported by the Austrian Science Fund (FWF): Y757Iborra, J.; Nishida, N.; Vidal Oriola, GF.; Yamada, A. (2015). Reducing relative termination to dependency pair problems. En Automated Deduction - CADE-25. Springer. 163-178. https://doi.org/10.1007/978-3-319-21401-6_11S163178Alarcón, B., Lucas, S., Meseguer, J.: A dependency pair framework for A $$\vee$$ C-termination. In: Ölveczky, P.C. (ed.) WRLA 2010. LNCS, vol. 6381, pp. 35–51. Springer, Heidelberg (2010)Arts, T., Giesl, J.: Termination of term rewriting using dependency pairs. Theor. Comput. Sci. 236(1–2), 133–178 (2000)Arts, T., Giesl, J.: A collection of examples for termination of term rewriting using dependency pairs. Technical report AIB-2001-09, RWTH Aachen (2001)Baader, F., Nipkow, T.: Term Rewriting and All That. Cambridge University Press, Cambridge (1998)Dershowitz, N.: Termination of rewriting. J. Symb. Comput. 3(1&2), 69–115 (1987)Endrullis, J., Waldmann, J., Zantema, H.: Matrix interpretations for proving termination of term rewriting. J. Autom. Reasoning 40(2–3), 195–220 (2008)Geser, A.: Relative termination. Dissertation, Fakultät für Mathematik und Informatik, Universität Passau, Germany (1990)Giesl, J., Kapur, D.: Dependency pairs for equational rewriting. In: Middeldorp, A. (ed.) RTA 2001. LNCS, vol. 2051, pp. 93–107. Springer, Heidelberg (2001)Giesl, J., Schneider-Kamp, P., Thiemann, R.: AProVE 1.2: automatic termination proofs in the dependency pair framework. In: Furbach, U., Shankar, N. (eds.) IJCAR 2006. LNCS (LNAI), vol. 4130, pp. 281–286. Springer, Heidelberg (2006)Giesl, J., Thiemann, R., Schneider-Kamp, P., Falke, S.: Mechanizing and improving dependency pairs. J. Autom. Reasoning 37(3), 155–203 (2006)Hirokawa, N., Middeldorp, A.: Polynomial interpretations with negative coefficients. In: Buchberger, B., Campbell, J. (eds.) AISC 2004. LNCS (LNAI), vol. 3249, pp. 185–198. Springer, Heidelberg (2004)Hirokawa, N., Middeldorp, A.: Dependency pairs revisited. In: van Oostrom, V. (ed.) RTA 2004. LNCS, vol. 3091, pp. 249–268. Springer, Heidelberg (2004)Hirokawa, N., Middeldorp, A.: Decreasing diagrams and relative termination. J. Autom. Reasoning 47(4), 481–501 (2011)Hullot, J.M.: Canonical forms and unification. CADE-5. LNCS, vol. 87, pp. 318–334. Springer, Heidelberg (1980)Iborra, J., Nishida, N., Vidal, G.: Goal-directed and relative dependency pairs for proving the termination of narrowing. In: De Schreye, D. (ed.) LOPSTR 2009. LNCS, vol. 6037, pp. 52–66. Springer, Heidelberg (2010)Kamin, S., Lévy, J.J.: Two generalizations of the recursive path ordering (1980, unpublished note)Klop, J.W.: Term rewriting systems: a tutorial. Bull. Eur. Assoc. Theor. Comput. Sci. 32, 143–183 (1987)Koprowski, A., Zantema, H.: Proving liveness with fairness using rewriting. In: Gramlich, B. (ed.) FroCos 2005. LNCS (LNAI), vol. 3717, pp. 232–247. Springer, Heidelberg (2005)Koprowski, A.: TPA: termination proved automatically. In: Pfenning, F. (ed.) RTA 2006. LNCS, vol. 4098, pp. 257–266. Springer, Heidelberg (2006)Korp, M., Sternagel, C., Zankl, H., Middeldorp, A.: Tyrolean termination tool 2. In: Treinen, R. (ed.) RTA 2009. LNCS, vol. 5595, pp. 295–304. Springer, Heidelberg (2009)Lankford, D.: Canonical algebraic simplification in computational logic. Technical report ATP-25, University of Texas (1975)Liu, J., Dershowitz, N., Jouannaud, J.-P.: Confluence by critical pair analysis. In: Dowek, G. (ed.) RTA-TLCA 2014. LNCS, vol. 8560, pp. 287–302. Springer, Heidelberg (2014)Nishida, N., Sakai, M., Sakabe, T.: Narrowing-based simulation of term rewriting systems with extra variables. ENTCS 86(3), 52–69 (2003)Nishida, N., Vidal, G.: Termination of narrowing via termination of rewriting. Appl. Algebra Eng. Commun. Comput. 21(3), 177–225 (2010)Ohlebusch, E.: Advanced Topics in Term Rewriting. Springer-Verlag, London (2002)Thiemann, R., Allais, G., Nagele, J.: On the formalization of termination techniques based on multiset orderings. In: RTA 2012. LIPIcs, vol. 15, pp. 339–354. Schloss Dagstuhl - Leibniz-Zentrum für Informatik (2012)Vidal, G.: Termination of narrowing in left-linear constructor systems. In: Garrigue, J., Hermenegildo, M.V. (eds.) FLOPS 2008. LNCS, vol. 4989, pp. 113–129. Springer, Heidelberg (2008)Yamada, A., Kusakari, K., Sakabe, T.: Nagoya termination tool. In: Dowek, G. (ed.) RTA-TLCA 2014. LNCS, vol. 8560, pp. 466–475. Springer, Heidelberg (2014)Yamada, A., Kusakari, K., Sakabe, T.: A unified ordering for termination proving. Sci. Comput. Program. (2014). doi: 10.1016/j.scico.2014.07.009Zantema, H.: Termination of term rewriting by semantic labelling. Fundamenta Informaticae 24(1/2), 89–105 (1995)Zantema, H.: Termination. In: Bezem, M., Klop, J.W., de Vrijer, R. (eds.) Term Rewriting Systems. Cambridge Tracts in Theoretical Computer Science, vol. 55, pp. 181–259. Cambridge University Press, Cambridge (2003

Biological effects of rinsing morsellised bone grafts before and after impaction

Rinsing bone grafts before or both before and after impaction might have different effects on the incorporation of the graft. Rinsing again after impaction might negatively influence bone induction if growth factors released by impaction are washed away. We studied if transforming growth factor-βs (TGF-βs) and bone morphogenetic proteins (BMPs) are released from the mineralised matrix by impaction and if these released growth factors induce osteogenic differentiation in human mesenchymal stem cells (hMSCs). Rinsed morsellised bone allografts were impacted in a cylinder and the escaping fluid was collected. The fluid was analysed for the presence of TGF-βs and BMPs, and the osteoinductive capacity was tested on hMSCs. Abundant TGF-β was present in the fluid. No BMPs could be detected. Osteogenic differentiation of hMSCs was inhibited by the fluid. Results from our study leave us only able to speculate whether rinsing grafts again after impaction has a beneficial effect on the incorporation process or not

Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical Tensions in HIV Treatment

The provision of effective antiretroviral therapy is an ethical imperative, and global access to antiretroviral drugs is an important aspect of this. The other less recognised aspect of effective HIV management is in ensuring that HIV does not become resistant to the drugs used in treatment (and increasingly also in prevention), as multi-drug resistant HIV poses a major threat to the sustainability of current responses to HIV control. In resource-constrained environments, the rapid scale up of access to life-saving anti-HIV treatment was achieved using a public health approach that standardised antiretroviral regimens, minimised laboratory monitoring, and devolved responsibilities from clinicians where necessary. In recent years demand for antiretroviral treatment has increased due to new understandings of the clinical importance of early treatment, but global investment has declined. Exponential growth of the population using antiretrovirals without careful monitoring increases the risk of significant antiretroviral drug resistance. In this chapter, I consider the example of single-drug interventions to prevent parent-to-child HIV transmission, and how the implementation of that strategy increased health risks for mothers. I argue that while global antiretroviral scale up must continue, laboratory monitoring at individual and national levels needs to improve to maintain treatment effectiveness, and protocols for moving people from failing regimens need to be strengthened