Towards understanding interactions between Sustainable Development Goals: the role of environment–human linkages

Only 10 years remain to achieve all Sustainable Development Goals (SDGs) globally, so there is a growing need to increase the effectiveness and efficiency of action by targeting multiple SDGs. The SDGs were conceived as an ‘indivisible whole’, but interactions between SDGs need to be better understood. Several previous assessments have begun to explore interactions including synergies and possible conflicts between the SDGs, and differ widely in their conclusions. Although some highlight the role of the more environmentally-focused SDGs in underpinning sustainable development, none specifically focuses on environment-human linkages. Assessing interactions between SDGs, and the influence of environment on them, can make an important contribution to informing decisions in 2020 and beyond. Here, we review previous assessments of interactions among SDGs, apply an influence matrix to assess pairwise interactions between all SDGs, and show how viewing these from the perspective of environment-human linkages can influence the outcome. Environment, and environment-human linkages, influence most interactions between SDGs. Our action-focused assessment enables decision makers to focus environmental management to have the greatest impacts, and to identify opportunities to build on synergies and reduce trade-offs between particular SDGs. It may enable sectoral decision makers to seek support from environment managers for achieving their goals. We explore cross-cutting issues and the relevance and potential application of our approach in supporting decision making for progress to achieve the SDGs

The Keck+Magellan Survey for Lyman Limit Absorption I: The Frequency Distribution of Super Lyman Limit Systems

We present the results of a survey for super Lyman limit systems (SLLS; defined to be absorbers with 19.0 <= log(NHI) <= 20.3 cm^-2) from a large sample of high resolution spectra acquired using the Keck and Magellan telescopes. Specifically, we present 47 new SLLS from 113 QSO sightlines. We focus on the neutral hydrogen frequency distribution f(N,X) of the SLLS and its moments, and compare these results with the Lyman-alpha forest and the damped Lyman alpha systems (DLA; absorbers with log(NHI) >= 20.3 cm^-2). We find that that f(N,X) of the SLLS can be reasonably described with a power-law of index alpha = -1.43^{+0.15}_{-0.16} or alpha = -1.19^{+0.20}_{-0.21} depending on whether we set the lower N(HI) bound for the analysis at 10^{19.0} cm^-2 or 10^{19.3}$ cm^-2, respectively. The results indicate a flattening in the slope of f(N,X) between the SLLS and DLA. We find little evidence for redshift evolution in the shape of f(N,X) for the SLLS over the redshift range of the sample 1.68 < z < 4.47 and only tentative evidence for evolution in the zeroth moment of f(N,X), the line density l_lls(X). We introduce the observable distribution function O(N,X) and its moment, which elucidates comparisons of HI absorbers from the Lyman-alpha through to the DLA. We find that a simple three parameter function can fit O(N,X) over the range 17.0 <= log(NHI) <=22.0. We use these results to predict that f(N,X) must show two additional inflections below the SLLS regime to match the observed f(N,X) distribution of the Lyman-alpha forest. Finally, we demonstrate that SLLS contribute a minor fraction (~15%) of the universe's hydrogen atoms and, therefore, an even small fraction of the mass in predominantly neutral gas.Comment: 15 pages, 10 figures, accepted to the Astrophysical Journal. Revision includes updated reference

BMI as a Modifiable Risk Factor for Type 2 Diabetes: Refining and Understanding Causal Estimates Using Mendelian Randomization.

This study focused on resolving the relationship between BMI and type 2 diabetes. The availability of multiple variants associated with BMI offers a new chance to resolve the true causal effect of BMI on type 2 diabetes; however, the properties of these associations and their validity as genetic instruments need to be considered alongside established and new methods for undertaking Mendelian randomization (MR). We explore the potential for pleiotropic genetic variants to generate bias, revise existing estimates, and illustrate value in new analysis methods. A two-sample MR approach with 96 genetic variants was used with three different analysis methods, two of which (MR-Egger and the weighted median) have been developed specifically to address problems of invalid instrumental variables. We estimate an odds ratio for type 2 diabetes per unit increase in BMI (kg/m(2)) of between 1.19 and 1.38, with the most stable estimate using all instruments and a weighted median approach (1.26 [95% CI 1.17, 1.34]). TCF7L2(rs7903146) was identified as a complex effect or pleiotropic instrument, and removal of this variant resulted in convergence of causal effect estimates from different causal analysis methods. This indicated the potential for pleiotropy to affect estimates and differences in performance of alternative analytical methods. In a real type 2 diabetes-focused example, this study demonstrates the potential impact of invalid instruments on causal effect estimates and the potential for new approaches to mitigate the bias caused.Medical Research Council (Grant IDs: MC_UU_12013/1, MC_UU_12013/2, MC_UU_12013/3); University of Bristol; Wellcome Trust (Grant ID: 100114); Medical Research Council (Methodology Research Fellowship, Grant ID: MR/N501906/1); Cancer Research UK (C18281/A19169).This is the author accepted manuscript. The final version is available from American Diabetes Association via http://dx.doi.org/10.2337/db16-041

The PCNA interaction protein box sequence in Rad54 is an integral part of its ATPase domain and is required for efficient DNA repair and recombination

Rad54 is an ATP-driven translocase involved in the genome maintenance pathway of homologous recombination (HR). Although its activity has been implicated in several steps of HR, its exact role(s) at each step are still not fully understood. We have identified a new interaction between Rad54 and the replicative DNA clamp, proliferating cell nuclear antigen (PCNA). This interaction was only mildly weakened by the mutation of two key hydrophobic residues in the highly-conserved PCNA interaction motif (PIP-box) of Rad54 (Rad54-AA). Intriguingly, the rad54-AA mutant cells displayed sensitivity to DNA damage and showed HR defects similar to the null mutant, despite retaining its ability to interact with HR proteins and to be recruited to HR foci in vivo. We therefore surmised that the PCNA interaction might be impaired in vivo and was unable to promote repair synthesis during HR. Indeed, the Rad54-AA mutant was defective in primer extension at the MAT locus as well as in vitro, but additional biochemical analysis revealed that this mutant also had diminished ATPase activity and an inability to promote D-loop formation. Further mutational analysis of the putative PIP-box uncovered that other phenotypically relevant mutants in this domain also resulted in a loss of ATPase activity. Therefore, we have found that although Rad54 interacts with PCNA, the PIP-box motif likely plays only a minor role in stabilizing the PCNA interaction, and rather, this conserved domain is probably an extension of the ATPase domain III

Global goals mapping: the environment-human landscape

The UK Natural Environment Research Council (NERC), The Rockefeller Foundation (RF), and the UK Economic and Social Research Council (ESRC) recognise that the development challenges of the 21st century require both a shift in thinking and actions that prepare us for the future, while enabling more effective development interventions today. These organisations are establishing a new initiative: 'Towards a Sustainable Earth: Environment-human Systems and the UN Global Goals' (TaSE) as part of their commitment to seeing the 17 Sustainable Development Goals (also known as Global Goals) become a reality. The core premise of the TaSE initiative is that environment-human interactions must be central to all development. The TaSE initiative is convening a meeting at The Rockefeller Foundation Bellagio Centre (7-11 November 2016) to identify the major research and innovation questions relevant to the achievement of the overarching ambition of this initiative. To help focus discussions during this meeting, NERC commissioned the Sussex Sustainability Research Programme (SSRP) at the University of Sussex and the UN Environment World Conservation Monitoring Centre (UNEP-WCMC) to produce a “synthesis of past and current research and innovation relating to the policy landscape surrounding the environment-human relationships and systems that interact across the UN Global Goals”. The commissioned work is encapsulated in this report, Global Goals mapping: the environment-human landscape. For each Goal, the first part of this report summarises the role of environment-human interactions and synthesises relevant research evidence, key innovations and policies, and knowledge and research gaps. The syntheses of research evidence, key innovations and policies presented for individual Global Goals show that environment-human interactions are important for the achievement of all of the Goals. However, the number of environment-human interactions, and the extent to which these interactions need to be considered for achieving each Goal, varies among Global Goals. Although research, innovation and policy have advanced substantially since the Millennium Ecosystem Assessment, knowledge and research gaps related to environment-human interactions remain for all Goals. The Global Goals were conceived as an 'indivisible whole'. The Goals relate to and depend on each other, but relationships between Goals need to be better understood. Previous analyses have begun to explore relationships including synergies and possible conflicts between the Goals from a number of different perspectives and differ widely in their conclusions. While many highlight the role of the more environmentally-focused Goals in underpinning sustainable development, none specifically focuses on environment-human interactions, which are the focus of the TaSE initiative and crucial to the achievement of the Goals. This report uses a new analysis to suggest which relationships between Global Goals may be most influenced by environment-human interactions. It is based on a pairwise view of relationships between Goals, assessing the influence that action (research, policy, innovation and/or management) towards one Goal may have on the potential for achieving others. It highlights 20 pairwise relationships between Goals where these influences may be especially strong, and illustrates for some of these how the knowledge and research gaps identified in Part 1 are relevant to the relationships between the Goals. In reality relationships among Goals are more complex and multidimensional than a pairwise analysis can illustrate, but visualising all connections among them is challenging. Further knowledge gaps and challenges related to the trade-offs, synergies and unintended consequences of the relationships among Goals will need to be addressed to achieve all 17 Goals. In order to understand relationships among Global Goals and prioritize action, including research, it is essential to consider multiple cross-cutting factors, including: temporal and spatial scales of action and impact; context for the action, whether local or other; the (multi) directionality of the relationships among Goals; thresholds and tipping points; number and types of people affected; human behaviour; governance, institutions and power; existence and accessibility of different types of knowledge; and the feasibility of obtaining and scaling-up research results and innovations by 2030. Several approaches have attempted to tackle interconnected challenges, including nexus thinking, pathways, leverage points, indigenous and local knowledge, integrated environmental assessments and integrated modelling. However, there is a need for more work and holistic approaches to achieve all 17 Goals. The syntheses of research evidence, innovations and policies regarding environment-human interactions relevant to each Global Goal and the analysis of the relationships among Goals provide a basis for identifying priority areas for new research, innovation and policy. The Bellagio Group has a vital role to play in building on this to help the TaSE initiative identify a research, innovation and research translation agenda in support of the Global Goals

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders

Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinic:polycytidylic acid (poly I:C) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly I:C elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF; referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly I:C-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation

The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K

Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity

A thematic analysis of factors influencing recruitment to maternal and perinatal trials

Background: Recruitment of eligible participants remains one of the biggest challenges to successful completion of randomised controlled trials (RCTs). Only one third of trials recruit on time, often requiring a lengthy extension to the recruitment period. We identified factors influencing recruitment success and potentially effective recruitment strategies. Methods: We searched MEDLINE and EMBASE from 1966 to December Week 2, 2006, the Cochrane Library Methodology Register in December 2006, and hand searched reference lists for studies of any design which focused on recruitment to maternal/perinatal trials, or if no studies of maternal or perinatal research could be identified, other areas of healthcare. Studies of nurses' and midwives' attitudes to research were included as none specifically about trials were located. We synthesised the data narratively, using a basic thematic analysis, with themes derived from the literature and after discussion between the authors. Results: Around half of the included papers (29/53) were specific to maternal and perinatal healthcare. Only one study was identified which focused on factors for maternal and perinatal clinicians and only seven studies considered recruitment strategies specific to perinatal research. Themes included: participant assessment of risk; recruitment process; participant understanding of research; patient characteristics; clinician attitudes to research and trials; protocol issues; and institutional or organisational issues. While no reliable evidence base for strategies to enhance recruitment was identified in any of the review studies, four maternal/perinatal primary studies suggest that specialised recruitment staff, mass mailings, physician referrals and strategies targeting minority women may increase recruitment. However these findings may only be applicable to the particular trials and settings studied. Conclusion: Although factors reported by both participants and clinicians which influence recruitment were quite consistent across the included studies, studies comparing different recruitment strategies were largely missing. Trials of different recruitment strategies could be embedded in large multicentre RCTs, with strategies tailored to the factors specific to the trial and institution.Rebecca L Tooher, Philippa F Middleton and Caroline A Crowthe

The hippocampus and entorhinal cortex encode the path and Euclidean distances to goals during navigation

BACKGROUND Despite decades of research on spatial memory, we know surprisingly little about how the brain guides navigation to goals. While some models argue that vectors are represented for navigational guidance, other models postulate that the future path is computed. Although the hippocampal formation has been implicated in processing spatial goal information, it remains unclear whether this region processes path- or vector-related information. RESULTS We report neuroimaging data collected from subjects navigating London's Soho district; these data reveal that both the path distance and the Euclidean distance to the goal are encoded by the medial temporal lobe during navigation. While activity in the posterior hippocampus was sensitive to the distance along the path, activity in the entorhinal cortex was correlated with the Euclidean distance component of a vector to the goal. During travel periods, posterior hippocampal activity increased as the path to the goal became longer, but at decision points, activity in this region increased as the path to the goal became closer and more direct. Importantly, sensitivity to the distance was abolished in these brain areas when travel was guided by external cues. CONCLUSIONS The results indicate that the hippocampal formation contains representations of both the Euclidean distance and the path distance to goals during navigation. These findings argue that the hippocampal formation houses a flexible guidance system that changes how it represents distance to the goal depending on the fluctuating demands of navigation