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

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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

Estimating geological CO2 storage security to deliver on climate mitigation

Carbon capture and storage (CCS) can help nations meet their Paris CO2 reduction commitments cost-effectively. However, lack of confidence in geologic CO2 storage security remains a barrier to CCS implementation. Here we present a numerical program that calculates CO2 storage security and leakage to the atmosphere over 10,000 years. This combines quantitative estimates of geological subsurface CO2 retention, and of surface CO2 leakage. We calculate that realistically well-regulated storage in regions with moderate well densities has a 50% probability that leakage remains below 0.0008% per year, with over 98% of the injected CO2 retained in the subsurface over 10,000 years. An unrealistic scenario, where CO2 storage is inadequately regulated, estimates that more than 78% will be retained over 10,000 years. Our modelling results suggest that geological storage of CO2 can be a secure climate change mitigation option, but we note that long-term behaviour of CO2 in the subsurface remains a key uncertainty

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

BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial.

BACKGROUND: Trials done in infants with low birthweight in west Africa suggest that BCG vaccination reduces all-cause mortality in the neonatal period, probably because of heterologous protection against non-tuberculous infections. This study investigated whether BCG alters all-cause infectious disease morbidity in healthy infants in a different high-mortality setting, and explored whether the changes are mediated via trained innate immunity. METHODS: This was an investigator-blind, randomised, controlled trial done at one hospital in Entebbe, Uganda. Infants who were born unwell (ie, those who were not well enough to be discharged directly home from the labour ward because they required medical intervention), with major congenital malformations, to mothers with HIV, into families with known or suspected tuberculosis, or for whom cord blood samples could not be taken, were excluded from the study. Any other infant well enough to be discharged directly from the labour ward was eligible for inclusion, with no limitation on gestational age or birthweight. Participants were recruited at birth and randomly assigned (1:1) to receive standard dose BCG 1331 (BCG-Danish) on the day of birth or at age 6 weeks (computer-generated randomisation, block sizes of 24, stratified by sex). Investigators and clinicians were masked to group assignment; parents were not masked. Participants were clinically followed up to age 10 weeks and contributed blood samples to one of three immunological substudies. The primary clinical outcome was physician-diagnosed non-tuberculous infectious disease incidence. Primary immunological outcomes were histone trimethylation at the promoter region of TNF, IL6, and IL1B; ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation; and transferrin saturation and hepcidin levels. All outcomes were analysed in the modified intention-to-treat population of all randomly assigned participants except those whose for whom consent was withdrawn. This trial is registered with the International Standard Randomised Controlled Trial Number registry (#59683017). FINDINGS: Between Sept 25, 2014, and July 31, 2015, 560 participants were enrolled and randomly assigned to receive BCG at birth (n=280) or age 6 weeks (n=280). 12 participants assigned to receive BCG at birth and 11 participants assigned to receive BCG at age 6 weeks were withdrawn from the study by their parents shortly after randomisation and were not included in analyses. During the first 6 weeks of life before the infants in the delayed vaccination group received BCG vaccination, physician-diagnosed non-tuberculous infectious disease incidence was lower in infants in the BCG at birth group than in the delayed group (98 presentations in the BCG at birth group vs 129 in the delayed BCG group; hazard ratio [HR] 0·71 [95% CI 0·53-0·95], p=0·023). After BCG in the delayed group (ie, during the age 6-10 weeks follow-up), there was no significant difference in non-tuberculous infectious disease incidence between the groups (88 presentations vs 76 presentations; HR 1·10 [0·87-1·40], p=0·62). BCG at birth inhibited the increase in histone trimethylation at the TNF promoter in peripheral blood mononuclear cells occurring in the first 6 weeks of life. H3K4me3 geometric mean fold-increases were 3·1 times lower at the TNF promoter (p=0·018), 2·5 times lower at the IL6 promoter (p=0·20), and 3·1 times lower at the IL1B promoter (p=0·082) and H3K9me3 geometric mean fold-increases were 8·9 times lower at the TNF promoter (p=0·0046), 1·2 times lower at the IL6 promoter (p=0·75), and 4·6 times lower at the IL1B promoter (p=0·068), in BCG-vaccinated (BCG at birth group) versus BCG-naive (delayed BCG group) infants. No clear effect of BCG on ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation, or transferrin saturation and hepcidin concentration, was detected (geometric mean ratios between 0·68 and 1·68; p≥0·038 for all comparisons). INTERPRETATION: BCG vaccination protects against non-tuberculous infectious disease during the neonatal period, in addition to having tuberculosis-specific effects. Prioritisation of BCG on the first day of life in high-mortality settings might have significant public-health benefits through reductions in all-cause infectious morbidity and mortality. FUNDING: Wellcome Trust. TRANSLATIONS: For the Luganda and Swahili translations of the abstract see Supplementary Materials section