Early metabolic adaptation in C57BL/6 mice resistant to high fat diet induced weight gain involves an activation of mitochondrial oxidative pathways

We investigated the short-term (7 days) and long-term (60 days) metabolic effect of high fat diet induced obesity (DIO) and weight gain in isogenic C57BL/6 mice and examined the specific metabolic differentiation between mice that were either strong-responders (SR), or non-responders (NR) to weight gain. Mice (n = 80) were fed a standard chow diet for 7 days prior to randomization into a high-fat (HF) (n = 56) or a low-fat (LF) (n = 24) diet group. The (1)H NMR urinary metabolic profiles of LF and HF mice were recorded 7 and 60 days after the diet switch. On the basis of the body weight gain (BWG) distribution of HF group, we identified NR mice (n = 10) and SR mice (n = 14) to DIO. Compared with LF, HF feeding increased urinary excretion of glycine conjugates of β-oxidation intermediate (hexanoylglycine), branched chain amino acid (BCAA) catabolism intermediates (isovalerylglycine, α-keto-β-methylvalerate and α-ketoisovalerate) and end-products of nicotinamide adenine dinucleotide (NAD) metabolism (N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide) suggesting up-regulation of mitochondrial oxidative pathways. In the HF group, NR mice excreted relatively more hexanoylglycine, isovalerylglycine, and fewer tricarboxylic acid (TCA) cycle intermediate (succinate) in comparison to SR mice. Thus, subtle regulation of ketogenic pathways in DIO may alleviate the saturation of the TCA cycle and mitochondrial oxidative metabolism.

What (science for) adaptation to climate change in Colombian agriculture? A commentary on “A way forward on adaptation to climate change in Colombian agriculture: perspectives towards 2050” by J. Ramirez-Villegas, M. Salazar, A. Jarvis, C. E. Navarro-Valcines.

Climate change is putting Colombian agriculture under significant stress and, if no adaptation is made, the latter will be severely impacted during the next decades. Ramirez-Villegas et al. (2012) set out a government-led, top-down, techno-scientific proposal for a way forward by which Colombian agriculture could adapt to climate change. However, this proposal largely overlooks the root causes of vulnerability of Colombian agriculture, and of smallholders in particular. I discuss some of the hidden assumptions underpinning this proposal and of the arguments employed by Ramirez-Villegas et al., based on existing literature on Colombian agriculture and the wider scientific debate on adaptation to climate change. While technical measures may play an important role in the adaptation of Colombian agriculture to climate change, I question whether the actions listed in the proposal alone and specifically for smallholders, truly represent priority issues. I suggest that by i) looking at vulnerability before adaptation, ii) contextualising climate change as one of multiple exposures, and iii) truly putting smallholders at the centre of adaptation, i.e. to learn about and with them, different and perhaps more urgent priorities for action can be identified. Ultimately, I argue that what is at stake is not only a list of adaptation measures but, more importantly, the scientific approach from which priorities for action are identified. In this respect, I propose that transformative rather than technical fix adaptation represents a better approach for Colombian agriculture and smallholders in particular, in the face of climate change.

Addressing uncertainty in adaptation planning for agriculture

We present a framework for prioritizing adaptation approaches at a range of timeframes. The framework is illustrated by four case studies from developing countries, each with associated characterization of uncertainty. Two cases on near-term adaptation planning in Sri Lanka and on stakeholder scenario exercises in East Africa show how the relative utility of capacity vs. impact approaches to adaptation planning differ with level of uncertainty and associated lead time. An additional two cases demonstrate that it is possible to identify uncertainties that are relevant to decision making in specific timeframes and circumstances. The case on coffee in Latin America identifies altitudinal thresholds at which incremental vs. transformative adaptation pathways are robust options. The final case uses three crop–climate simulation studies to demonstrate how uncertainty can be characterized at different time horizons to discriminate where robust adaptation options are possible. We find that impact approaches, which use predictive models, are increasingly useful over longer lead times and at higher levels of greenhouse gas emissions. We also find that extreme events are important in determining predictability across a broad range of timescales. The results demonstrate the potential for robust knowledge and actions in the face of uncertainty.

Observed adaptation to climate change as initiated transition

This paper investigates whether and to what extent a wide range of actors in the UK are adapting to climate change, and whether this is evidence of a social transition. We document evidence of over 300 examples of early adopters of adaptation practice to climate change in the UK. These examples span a range of activities from small adjustments (or coping), to building adaptive capacity, to implementing actions and to creating deeper systemic change in public and private organisations in a range of sectors. We find that adaptation in the UK has been dominated by government initiatives and has principally occurred in the form of research into climate change impacts. These government initiatives have stimulated a further set of actions at other scales in public agencies, regulatory agencies and regional government (and the devolved administrations), though with little real evidence of climate change adaptation initiatives trickling down to local government level. The sectors requiring significant investment in large scale infrastructure have invested more heavily than those that do not in identifying potential impacts and adaptations. Thus we find a higher level of adaptation activity by the water supply and flood defence sectors. Sectors that are not dependent on large scale infrastructure appear to be investing far less effort and resources in preparing for climate change. We conclude that the UK government-driven top-down targeted adaptation approach has generated anticipatory action at low cost in some areas. We also conclude that these actions may have created enough niche activities to allow for diffusion of new adaptation practices in response to real or perceived climate change. These results have significant implications for how climate policy can be developed to support autonomous adaptors in the UK and other countries.

Building dynamic capabilities of adaptation and innovation: a study of micro-foundations in a transition economy

What are the microfoundations of dynamic capabilities that sustain competitive advantage in a highly volatile environment, such as a transition economy? We explore the detailed nature of these dynamic capabilities along with their antecedents by tracing the sequence of their development based on a longitudinal case study of an organization subject to an external context of radical transition — the Russian oil company, Yukos. Our rich qualitative data indicate two distinct types of dynamic capabilities that are pivotal for organizational transformation. Adaptation dynamic capabilities relate to routines of resource exploitation and deployment, which are supported by acquisition, internalization and dissemination of extant knowledge, as well as resource reconfiguration, divestment and integration. Innovation dynamic capabilities relate to the creation of completely new capabilities via exploration and path-creation processes, which are supported by search, experimentation and risk taking, as well as project selection, funding and implementation. Second, we find that sequencing the two types of dynamic capabilities, helped the organization both to secure short-term competitive advantage, and to create the basis for long-term competitive advantage. These dynamic capability constructs advance theoretical understanding of what dynamic capabilities are, whilst their sequencing explains how firms create, leverage and enhance them over time.

An epigenetic signature of developmental potential in neural stem cells and early neurons.

A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential. Here, we have interrogated the epigenome during differentiation of ESC-derived NSCs to immature GABAergic interneurons. We show that developmental transitions are accompanied by loss of bivalency at many promoters in line with their increasing developmental restriction from pluripotent ESC through multipotent NSC to committed GABAergic interneuron. At the NSC stage, the promoters of genes encoding many transcriptional regulators required for differentiation of multiple neuronal subtypes and neural crest appear to be bivalent, consistent with the broad developmental potential of NSCs. Upon differentiation to GABAergic neurons, all non-GABAergic promoters resolve to H3K27me3 monovalency, whereas GABAergic promoters resolve to H3K4me3 monovalency or retain bivalency. Importantly, many of these epigenetic changes occur before any corresponding changes in gene expression. Intriguingly, another group of gene promoters gain bivalency as NSCs differentiate toward neurons, the majority of which are associated with functions connected with maturation and establishment and maintenance of connectivity. These data show that bivalency provides a dynamic epigenetic signature of developmental potential in both NSCs and in early neurons. Stem Cells 2013;31:1868-1880.

REST: transcriptional and epigenetic regulator

Acquisition and maintenance of cell fate and potential are dependent on the complex interplay of extracellular signaling, gene regulatory networks and epigenetic states. During embryonic development, embryonic stem cells become progressively more restricted along specific lineages, ultimately giving rise to the diversity of cell types in the adult mammalian organism. Recent years have seen major advances in our understanding of the mechanisms that regulate the underlying transcriptional programmes during development. In particular, there has been a significant increase in our knowledge of how epigenetic marks on chromatin can regulate transcription by generating more or less permissive chromatin conformations. This article focuses on how a single transcription factor, repressor element-1 silencing transcription factor, can function as both a transcriptional and epigenetic regulator, controlling diverse aspects of development. We will discuss how the elucidation of repressor element-1 silencing transcription factor function in both normal and disease conditions has provided valuable insights into how the epigenome and transcriptional regulators might cooperatively orchestrate correct development.

The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

The STRATADAPT scale: a measure of marketing strategy adaptation to international business markets

Purpose – The development of marketing strategies optimally adjusted to export markets has been a vitally important topic for both managers and academics for about five decades. However, there is no agreement in the literature about which elements integrate marketing strategy and which components of domestic strategies should be adapted to export markets. The purpose of this paper is to develop a new scale – STRATADAPT. Design/methodology/approach – Results from a sample of small and medium-sized industrial exporting firms support a four-dimensional scale – product, promotion, price, and distribution strategies – of 30 items. The scale presents evidence of composite reliability as well as discriminant and nomological validity. Findings – Findings reveal that all four dimensions of marketing strategy adaptation are positively associated with the amount of the firm's financial resources allocated to export activity. Practical implications – The STRATADAPT scale may assist managers in developing better international marketing strategies as well as in planning more accurate and efficient marketing programs across markets. Originality/value – This study develops a new scale, the STRATADAPT scale, which is a broad measure of export marketing strategy adaptation.

Detection of Oxidation Products of 5-Methyl-2′-Deoxycytidine in Arabidopsis DNA

Epigenetic regulations play important roles in plant development and adaptation to environmental stress. Recent studies from mammalian systems have demonstrated the involvement of ten-eleven translocation (Tet) family of dioxygenases in the generation of a series of oxidized derivatives of 5-methylcytosine (5-mC) in mammalian DNA. In addition, these oxidized 5-mC nucleobases have important roles in epigenetic remodeling and aberrant levels of 5-hydroxymethyl-29-deoxycytidine (5-HmdC) were found to be associated with different types of human cancers. However, there is a lack of evidence supporting the presence of these modified bases in plant DNA. Here we reported the use of a reversed-phase HPLC coupled with tandem mass spectrometry method and stable isotope-labeled standards for assessing the levels of the oxidized 5-mC nucleosides along with two other oxidatively induced DNA modifications in genomic DNA of Arabidopsis. These included 5- HmdC, 5-formyl-29-deoxycytidine (5-FodC), 5-carboxyl-29-deoxycytidine (5-CadC), 5-hydroxymethyl-29-deoxyuridine (5- HmdU), and the (59S) diastereomer of 8,59-cyclo-29-deoxyguanosine (S-cdG). We found that, in Arabidopsis DNA, the levels of 5-HmdC, 5-FodC, and 5-CadC are approximately 0.8 modifications per 106 nucleosides, with the frequency of 5-HmdC (per 5-mdC) being comparable to that of 5-HmdU (per thymidine). The relatively low levels of the 5-mdC oxidation products suggest that they arise likely from reactive oxygen species present in cells, which is in line with the lack of homologous Tetfamily dioxygenase enzymes in Arabidopsis.

Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells

Background: Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. Materials and methods: MCF-7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal-stripped serum with 10-8 M 17-oestradiol and 10 g/ml insulin (stock 1), 10-8 M 17-oestradiol (stock 2), 10 g/ml insulin (stock 3) or no addition (stock 4). Results: Loss of growth response to oestrogen was observed only in stock 4 cells. Long-term maintenance with insulin in the absence of oestradiol (stock 3) resulted in raised oestrogen receptor alpha (ERlevels (measured by western immunoblotting) and development of hypersensitivity (assayed by oestrogen-responsive reporter gene induction and dose response to oestradiol for proliferation under serum-free conditions), but with no loss of growth response to oestrogen. Conclusion: Hypersensitivity can develop without any growth adaptation and therefore is not a prerequisite for loss of growth response in MCF-7 cells.

Strong armies, slow adaptation: civil-military relations and diffusion of military power

Why are some states more willing to adopt military innovations than others? Why, for example, were the great powers of Europe able to successfully reform their military practices to better adapt to and participate in the so-called military revolution of the sixteenth and seventeenth centuries while their most important extra-European competitor, the Ottoman Empire, failed to do so? This puzzle is best explained by two factors: civil-military relations and historical timing. In the Ottoman Empire, the emergence of an institutionally strong and internally cohesive army during the early stages of state formation—in the late fourteenth century—equipped the military with substantial bargaining powers. In contrast, the great powers of Europe drew heavily on private providers of military power during the military revolution and developed similar armies only by the second half of the seventeenth century, limiting the bargaining leverage of European militaries over their rulers. In essence, the Ottoman standing army was able to block reform efforts that it believed challenged its parochial interests. Absent a similar institutional challenge, European rulers initiated military reforms and motivated officers and military entrepreneurs to participate in the ongoing military revolution.