Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system

A central process in evolution is the recruitment of genes to regulatory networks. We engineered immotile strains of the bacterium Pseudomonas fluorescens that lack flagella due to deletion of the regulatory gene fleQ. Under strong selection for motility, these bacteria consistently regained flagella within 96 hours via a two-step evolutionary pathway. Step 1 mutations increase intracellular levels of phosphorylated NtrC, a distant homologue of FleQ, which begins to commandeer control of the fleQ regulon at the cost of disrupting nitrogen uptake and assimilation. Step 2 is a switch-of-function mutation that redirects NtrC away from nitrogen uptake and towards its novel function as a flagellar regulator. Our results demonstrate that natural selection can rapidly rewire regulatory networks in very few, repeatable mutational steps.

Transcription factor NF-kappaB is transported to the nucleus via cytoplasmic dynein/dynactin motor complex in hippocampal neurons

Background Long-term changes in synaptic plasticity require gene transcription, indicating that signals generated at the synapse must be transported to the nucleus. Synaptic activation of hippocampal neurons is known to trigger retrograde transport of transcription factor NF-κB. Transcription factors of the NF-κB family are widely expressed in the nervous system and regulate expression of several genes involved in neuroplasticity, cell survival, learning and memory. Principal Findings In this study, we examine the role of the dynein/dynactin motor complex in the cellular mechanism targeting and transporting activated NF-κB to the nucleus in response to synaptic stimulation. We demonstrate that overexpression of dynamitin, which is known to dissociate dynein from microtubules, and treatment with microtubule-disrupting drugs inhibits nuclear accumulation of NF-κB p65 and reduces NF-κB-dependent transcription activity. In this line, we show that p65 is associated with components of the dynein/dynactin complex in vivo and in vitro and that the nuclear localization sequence (NLS) within NF-κB p65 is essential for this binding. Conclusion This study shows the molecular mechanism for the retrograde transport of activated NF-κB from distant synaptic sites towards the nucleus.

Focus on environmental risks and migration: causes and consequences

Environmental change poses risks to societies, including disrupting social and economic systems such as migration. At the same time, migration is an effective adaptation to environmental and other risks. We review novel science on interactions between migration, environmental risks and climate change. We highlight emergent findings, including how dominant flows of rural to urban migration mean that populations are exposed to new risks within destination areas and the requirement for urban sustainability. We highlight the issue of lack of mobility as a major issue limiting the effectiveness of migration as an adaptation strategy and leading to potentially trapped populations. The paper presents scenarios of future migration that show both displacement and trapped populations over the incoming decades. Papers in the special issue bring new insights from demography, human geography, political science and environmental science to this emerging field.

On the evolutionary origins of obesity: a new hypothesis

Obesity is an escalating threat of pandemic proportions, currently affecting billions of people worldwide and exerting a devastating socioeconomic influence in industrialized countries. Despite intensive efforts to curtail obesity, results have proved disappointing. Although it is well recognized that obesity is a result of gene-environment interactions and that predisposition to obesity lies predominantly in our evolutionary past, there is much debate as to the precise nature of how our evolutionary past contributed to obesity. The “thrifty genotype” hypothesis suggests that obesity in industrialized countries is a throwback to our ancestors having undergone positive selection for genes that favored energy storage as a consequence of the cyclical episodes of famine and surplus after the advent of farming 10 000 years ago. Conversely, the “drifty genotype” hypothesis contends that the prevalence of thrifty genes is not a result of positive selection for energy-storage genes but attributable to genetic drift resulting from the removal of predative selection pressures. Both theories, however, assume that selection pressures the ancestors of modern humans living in western societies faced were the same. Moreover, neither theory adequately explains the impact of globalization and changing population demographics on the genetic basis for obesity in developed countries, despite clear evidence for ethnic variation in obesity susceptibility and related metabolic disorders. In this article, we propose that the modern obesity pandemic in industrialized countries is a result of the differential exposure of the ancestors of modern humans to environmental factors that began when modern humans left Africa around 70 000 years ago and migrated through the globe, reaching the Americas around 20 000 years ago. This article serves to elucidate how an understanding of ethnic differences in genetic susceptibility to obesity and the metabolic syndrome, in the context of historic human population redistribution, could be used in the treatment of obesity in industrialized countries

Orexin restores aging-related brown adipose tissue dysfunction in male mice

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with interscapular BAT morphologic abnormalities and thermogenic dysfunction. In vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphologic characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy. Our results suggest a role for orexin (OX) signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass were accelerated in mice in which OX-producing neurons were ablated. Conversely, OX injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.

El Niño 2015/2016 impact analysis, monthly outlook November 2015

During the summer and autumn 2015, El Niño conditions in the east and central Pacific have strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during this summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g., droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g., health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work providing information from seasonal forecast models to give a more detailed monthly outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of a monthly outlook column. This monthly outlook is an indication of the average likely conditions for that month and region and is not a definite prediction of weather impacts.

El Niño 2015/2016 impact analysis, monthly outlook December 2015

During the summer and autumn 2015, El Niño conditions in the east and central Pacific have strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during this summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g. droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g. health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work providing information from observations and seasonal forecast models to give a more detailed outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of an ‘Observations and Outlook’ row. This consists of observational information for the past seasons of JJA 2015 and SON 2015, a detailed monthly outlook from 5 modeling centres for Dec 2015 and then longer-term seasonal forecast information from 2 modeling centres for the future seasons of JF 2016 and MAM 2016. The seasonal outlook information is an indication of the average likely conditions for that coming month (or season) and region and is not a definite prediction of weather impacts.

El Niño 2015/2016 impact analysis, monthly outlook January 2016

During the summer and autumn of 2015, El Niño conditions in the east and central Pacific have strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during this summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g., droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g., health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work providing information from observations and seasonal forecast models to give a more detailed outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of an ‘Observations and Outlook’ row. This consists of observational information for the past seasons of JJA 2015, SON 2015 and Dec 2015, a detailed monthly outlook from 4 modeling centres for Jan 2016 and then longer-term seasonal forecast information from 2 modeling centres for the future seasons of Feb 2016, MAM 2016 and Jun 2016. The seasonal outlook information is an indication of the average likely conditions for that coming month (or season) and region and is not a definite prediction of weather impacts.

El Niño 2015/2016 impact analysis, monthly outlook February 2016

During the summer and autumn of 2015, El Niño conditions in the east and central Pacific strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during the summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g., droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g., health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work, providing information from observations and seasonal forecast models to give a more detailed outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of an ‘Observations and Outlook’ row. This consists of observational information for the past seasons of JJA 2015, SON 2015 and DJ 2015/2016, a detailed monthly outlook from 5 modeling centres for Feb 2016 and then longer-term seasonal forecast information from 2 modeling centres for the future seasons of MAM 2016 and JJ 2016. The seasonal outlook information is an indication of the average likely conditions for that coming month (or season) and region and is not a definite prediction of weather impacts. This report has been produced by University of Reading for Evidence on Demand with the assistance of the UK Department for International Development (DFID) contracted through the Climate, Environment, Infrastructure and Livelihoods Professional Evidence and Applied Knowledge Services (CEIL PEAKS) programme, jointly managed by DAI (which incorporates HTSPE Limited) and IMC Worldwide Limited.

Retinoid-Related Receptor (ROR) alpha mRNA Expression Is Altered in the Brain of Male Mice Lacking All Ligand-Binding Thyroid Hormone Receptor (TR) Isoforms

In the vertebrate brain, the thalamus serves as a relay and integration station for diverse neuronal information en route from the periphery to the cortex. Deficiency of TH during development results in severe cerebral abnormalities similar to those seen in the mouse when the retinoic acid receptor (ROR)α gene is disrupted. To investigate the effect of the thyroid hormone recep-tors (TRs) on RORalpha gene expression, we used intact male mice, in which the genes encoding the α and beta TRs have been deleted. In situ hybridization for RORalpha mRNA revealed that this gene is expressed in specific areas of the brain including the thalamus, pons, cerebellum, cortex, and hippocampus. Our quantitative data showed differences in RORalpha mRNA expression in different subthalamic nuclei between wild-type and knock-out mice. For example, the centromedial nucleus of the thalamus, which plays a role in mediating nociceptive and visceral information from the brainstem to the basal ganglia and cortical regions, has less expression of RORalpha mRNA in the knockout mice (-37%) compared to the wild-type controls. Also, in the dorsal geniculate (+72%) and lateral posterior nuclei (+58%) we found more RORalpha mRNA in dKO as compared to dWT animals. Such differences in RORalpha mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Estrogens and thyroid hormone: Non-genomic effects are coupled to transcription.

Estrogens and thyroid hormones are regulators of important diverse physiological processes such as reproduction, thermogenesis, neural development, neural differentiation and cardiovascular functions. Both are ligands for receptors in the nuclear receptor superfamily, which act as ligand-dependent transcription factors, regulating transcription. However, estrogens and thyroid hormones also rapidly (within minutes or seconds) activate kinase cascades and calcium increases, presumably initiated at the cell membrane. We discuss the relevance of both modes of hormone action, including the membrane estrogen receptor, to physiology, with particular reference to lordosis behavior. We first showed that estrogen restricted to the membrane can, in fact, lead to subsequent increases in transcription from a consensus estrogen response element-based reporter in the neuroblastoma cell line, SK-N-BE(2)C. Using a novel hormonal paradigm, we also showed that the activation of protein kinase A, protein kinase C, mitogen activated protein kinase and increases in calcium were important in the ability of the membrane-limited estrogen to potentiate transcription. We discuss the source of calcium important in transcriptional potentiation. Since estrogens and thyroid hormones have common effects on neuroprotection, cognition and mood, we also hypothesized that crosstalk could occur between the rapid actions of thyroid hormones and the genomic actions of estrogens. In neural cells, we showed that triiodothyronine acting rapidly via MAPK can increase transcription by the nuclear estrogen receptor ERa from a consensus estrogen response element, possibly by the phosphorylation of the ERa. Novel mechanisms that link signals initiated by hormones from the membrane to the nucleus are physiologically relevant and can achieve neuroendocrine integration

Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles

Hormonal ligands for the nuclear receptor superfamily have at least two interacting mechanisms of action: 1) classical transcriptional regulation of target genes (genomic mechanisms); and 2) nongenomic actions that are initiated at the cell membrane, which could impact transcription. Although transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. Historically, this has led to a considerable divergence of thought in the molecular endocrine field. We have attempted to uncover principles of hormone action that are relevant to membrane-initiated actions of estrogens. There is evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium. Membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription. These signaling cascades may occur in parallel or in series but subsequently converge at the level of modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription. The idea of synergistic coupling between membrane-initiated and genomic actions of hormones fundamentally revises the paradigms of cell signaling in neuroendocrinology.

Non-genomic actions of estrogens and their interaction with genomic actions in the brain

Ligands for the nuclear receptor superfamily have at least two mechanisms of action: (a) classical transcriptional regulation of target genes (genomic mechanisms); and (b) non-genomic actions, which are initiated at the cell membrane, which could also impact transcription. Though transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. This has led to considerable debate over the physiological relevance of membrane-initiated actions of hormones versus genomic actions of hormones, with genomic actions predominating in the endocrine field. There is good evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium and that these are linked to physiologically relevant scenarios in the brain. We show evidence in this review, that membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription in both the central nervous system and in non-neuronal cell lines. We present a theoretical scenario which can be used to understand this phenomenon. These signaling cascades may occur in parallel or in series but subsequently, converge at the modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other non-cognate hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription, though the relevance of this is less clear. The idea that coupling between membrane-initiated and genomic actions of hormones is a novel idea in neuroendocrinology and provides us with a unified view of hormone action in the central nervous system.

Cognition and anxiety are regulated by thyroid hormone signaling

Anxiety and cognition are both linked to deficits in thyroid hormone concentrations in humans and in rodent models. Both processes have also been shown to be affected by the loss of the thyroid hormone receptors (TR) or by mutant transgenic TRs. Specifically, the unbalanced action of the unliganded TRα1 is thought to be important in the memory deficit and extreme anxiety seen in transgenic mice. The contribution of TRβ is less well defined and the molecular mechanisms that underlie these deficits are also unknown. We review the literature that demonstrates the importance of the thyroid hormone (TH) and the TR in these processes and focus on the mechanisms, in particular adult hippocampal neurogenesis in the dentate gyrus, that might be important in mediating both state anxiety and cognition by thyroid hormone.