Sustainability indicators are well recognized for their potential to assess and monitor sustainable development of agricultural systems. A large number of indicators are proposed in various sustainability assessment frameworks, which raises concerns regarding the validity of approaches, usefulness and trust in such frameworks. Selecting indicators requires transparent and well-defined procedures to ensure the relevance and validity of sustainability assessments. The objective of this study, therefore, was to determine whether 123Environ Dev Sustain DOI 10.1007/s10668-016-9803-x experts agree on which criteria are most important in the selection of indicators and indicator sets for robust sustainability assessments. Two groups of experts (Temperate Agriculture Research Network and New Zealand Sustainability Dashboard) were asked to rank the relative importance of eleven criteria for selecting individual indicators and of nine criteria for balancing a collective set of indicators. Both ranking surveys reveal a startling lack of consensus amongst experts about how best to measure agricultural sustainability and call for a radical rethink about how complementary approaches to sustainability assessments are used alongside each other to ensure a plurality of views and maximum collaboration and trust amongst stakeholders. To improve the transparency, relevance and robustness of sustainable assessments, the context of the sustainability assessment, including prioritizations of selection criteria for indicator selection, must be accounted for. A collaborative design process will enhance the acceptance of diverse values and prioritizations embedded in sustainability assessments. The process by which indicators and sustainability frameworks are established may be a much more important determinant of their success than the final shape of the assessment tools. Such an emphasis on process would make assessments more transparent, transformative and enduring.
We characterized HIV-1 reverse transcriptase (RT) variants either with or without the (؊)-2,3-deoxy-3-thiacytidine-resistant M184I mutation isolated from a single HIV-1 infected patient. First, unlike variants with wild-type M184, M184I RT variants displayed significantly reduced DNA polymerase activity at low dNTP concentrations, which is indicative of reduced dNTP binding affinity. Second, the M184I variant displayed a ϳ10-to 13-fold reduction in dNTP binding affinity, compared with the Met-184 variant. However, the k pol values of these two RTs were similar. Third, unlike HIV-1 vectors with wild-type RT, the HIV-1 vector harboring M184I RT failed to transduce cell types containing low dNTP concentrations, such as human macrophage, likely due to the reduced DNA polymerization activity of the M184I RT under low cellular dNTP concentration conditions. Finally, we compared the binary complex structures of wild-type and M184I RTs. The Ile mutation at position 184 with a longer and more rigid -branched side chain, which was previously known to alter the RT-template interaction, also appears to deform the shape of the dNTP binding pocket. This can restrict ground state dNTP binding and lead to inefficient DNA synthesis particularly at low dNTP concentrations, ultimately contributing to viral replication failure in macrophage and instability in vivo of the M184I mutation.(Ϫ)-2Ј,3Ј-Deoxy-3Ј-thiacytidine (3TC), 3 a deoxycytidine analog reverse transcriptase (RT) inhibitor, has been routinely included in the anti-HIV-1 drug regime (1, 2). During 3TC therapy, two amino acid substitutions at position 184 of RT are sequentially selected, conferring viral resistance to this drug. The M184I mutation is detected earlier, and eventually replaced with the M184V mutation. One initial explanation for the delayed selection of the M184V mutation is the requirement of two nucleotide mutations to develop the final M184V mutation from the wild-type methionine codon (ATG). In contrast, the M184I mutation requires only a single nucleotide mutation from the Met codon, which may result in its early selection during 3TC therapy (3-7).Structural analysis later provided a functional explanation for the instability in vivo of the M184I mutation. The M184I mutation alters the RT interaction with the template nucleotide more significantly than the M184V mutation, leading to more severely decreased processivity, compared with the M184V RT (8). Indeed, the distributive DNA synthesis catalyzed by the M184I RT has been a major explanation for the instability in vivo of this mutation and its rapid transition to the M184V mutation. The long -branched side chains of these two mutations efficiently block the entry of 3TCTP to the active site (8, 9). Interestingly, pre-steady-state kinetic studies of the M184V mutant demonstrated that the M184V mutation only slightly (1-to 2-fold) affects K d (dNTP binding affinity), but not k pol (conformational change/chemical catalysis) steps of HIV-1 RT with normal dNTP substrates, implying that the Val mutation d...
The human microbiome is an important emergent area of cross, multi and transdisciplinary study. The complexity of this topic leads to conflicting narratives and regulatory challenges. It raises questions about the benefits of its commercialisation and drives debates about alternative models for engaging with its publics, patients and other potential beneficiaries. The social sciences and the humanities have begun to explore the microbiome as an object of empirical study and as an opportunity for theoretical innovation. They can play an important role in facilitating the development of research that is socially relevant, that incorporates cultural norms and expectations around microbes and that investigates how social and biological lives intersect. This is a propitious moment to establish lines of collaboration in the study of the microbiome that incorporate the concerns and capabilities of the social sciences and the humanities together with those of the natural sciences and relevant stakeholders outside academia. This paper presents an agenda for the engagement of the social sciences with microbiome research and its implications for public policy and social change. Our methods were informed by existing multidisciplinary science-policy agenda-setting exercises. We recruited 36 academics and stakeholders and asked them to produce a list of important questions about the microbiome that were in need of further social science research. We refined this initial list into an agenda of 32 questions and organised them into eight themes that both complement and extend existing research trajectories. This agenda was further developed through a structured workshop where 21 of our participants refined the agenda and reflected on the challenges and the limitations of the exercise itself. The agenda identifies the need for research that addresses the implications of the human microbiome for human health, public health, public and private sector research and notions of self and identity. It also suggests new lines of research sensitive to the complexity and heterogeneity of human–microbiome relations, and how these intersect with questions of environmental governance, social and spatial inequality and public engagement with science.
The incidence of mixed viral/bacterial infections has increased recently because of the dramatic increase in antibiotic‐resistant strains, the emergence of new pathogens, and the resurgence of old ones. Despite the relatively well‐known role of viruses in enhancing bacterial infections, the impact of bacterial infections on viral infections remains unknown. In this study, we provide direct evidence that nontypeable Haemophilus influenzae (NTHi), a major respiratory bacterial pathogen, augments the host antiviral response by up‐regulating epithelial Toll‐like receptor 7 (TLR7) expression in vitro and in vivo. Moreover, NTHi induces TLR7 expression via a TLR2‐MyD88‐IRAK‐TRAF6‐IKK‐NF‐κB‐dependent signaling pathway. Interestingly, CYLD, a novel deubiquitinase, acts as a negative regulator of TLR7 induction by NTHi. Our study thus provides new insights into a novel role for bacterial infection in enhancing host antiviral response and further identifies CYLD for the first time as a critical negative regulator of host antiviral response.
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