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"Arthur, H"
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Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?
Key Points
Spinal muscular atrophy (SMA) is caused by reduced amounts of the ubiquitously expressed survival motor neuron protein (SMN). SMN functions in RNA metabolism, but the question of which aspect of its function is disrupted to give a motor neuron disease remains unanswered.
SMN functions in the assembly of Sm proteins onto small nuclear RNAs (snRNAs) during pre-mRNA splicing. It has been suggested that SMN might have a role in the assembly of other ribonucleoprotein (RNP) complexes.
SMA is caused by loss or mutation of
SMN1
and retention of
SMN2
,leading to low SMN levels. Proteins that carry mild missense mutations complement
SMN2
to restore assembly activity and give a mild phenotype.
Loss of SMN in all species results in lethality, indicating that SMN has an essential function. Animal models of SMA can be created by reducing the levels of SMN.
It has been proposed that reduction of SMN levels results in an alteration of the small nuclear ribonucleoprotein (snRNP) profile. This is supported by the correlation between snRNP assembly activity and SMA severity in mice; however, a clear indication of the downstream target genes that are affected is currently lacking.
SMN is found in axons of cultured cells, and a second hypothesis suggests that altered mRNA transport in axons may contribute to SMA. However, a clear indication of what SMN function is disrupted to alter mRNA transport is lacking.
SMN functions in the assembly of RNPs, but it remains unresolved whether it is an axonal or an snRNP component that is disrupted in SMA. Experiments showing a clear suppression of the phenotype by manipulating a particular pathway could be used to demonstrate the crucial pathway in SMA.
How a reduction in the level of a ubiquitously expressed protein, SMN, causes the motor neuron–specific deficits that characterize spinal muscular atrophy is unknown. Burghes and Beattie discuss the function of SMN and the debate concerning the crucial pathways disrupted in SMA.
Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene (
SMN1
), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA.
Journal Article
Global riverine N and P transport to ocean increased during the 20th century despite increased retention along the aquatic continuum
Various human activities – including agriculture, water consumption, river damming, and aquaculture – have intensified over the last century. This has had a major impact on nitrogen (N) and phosphorus (P) cycling in global continental waters. In this study, we use a coupled nutrient-input–hydrology–in-stream nutrient retention model to quantitatively track the changes in the global freshwater N and P cycles over the 20th century. Our results suggest that, during this period, the global nutrient delivery to streams increased from 34 to 64 Tg N yr−1 and from 5 to 9 Tg P yr−1. Furthermore, in-stream retention and removal grew from 14 to 27 Tg N yr−1 and 3 to 5 Tg P yr−1. One of the major causes of increased retention is the growing number of reservoirs, which now account for 24 and 22 % of global N and P retention/removal in freshwater systems, respectively. This increase in nutrient retention could not balance the increase in nutrient delivery to rivers with the consequence that river nutrient transport to the ocean increased from 19 to 37 Tg N yr−1 and from 2 to 4 Tg P yr−1. Human activities have also led to a global increase in the molar N : P ratio in freshwater bodies.
Journal Article
Oxygen limitation may affect the temperature and size dependence of metabolism in aquatic ectotherms
Both oxygen and temperature are fundamental factors determining metabolic performance, fitness, ecological niches, and responses of many aquatic organisms to climate change. Despite the importance of physical and physiological constraints on oxygen supply affecting aerobic metabolism of aquatic ectotherms, ecological theories such as the metabolic theory of ecology have focused on the effects of temperature rather than oxygen. This gap currently impedes mechanistic models from accurately predicting metabolic rates (i.e., oxygen consumption rates) of aquatic organisms and restricts predictions to resting metabolism, which is less affected by oxygen limitation. Here, we expand on models of metabolic scaling by accounting for the role of oxygen availability and temperature on both resting and active metabolic rates. Our model predicts that oxygen limitation is more likely to constrain metabolism in larger, warmer, and active fish. Consequently, active metabolic rates are less responsive to temperature than are resting metabolic rates, and metabolism scales to body size with a smaller exponent whenever temperatures or activity levels are higher. Results from a metaanalysis of fish metabolic rates are consistent with our model predictions. The observed interactive effects of temperature, oxygen availability, and body size predict that global warming will limit the aerobic scope of aquatic ectotherms and may place a greater metabolic burden on larger individuals, impairing their physiological performance in the future. Our model reconciles the metabolic theory with empirical observations of oxygen limitation and provides a formal, quantitative framework for predicting both resting and active metabolic rate and hence aerobic scope of aquatic ectotherms.
Journal Article
مدخل إلى الفلسفة القديمة
تشكل الفلسفة الإغريقية محاولة الإنسان الأولى لتفسير العالم بالأدوات العقلية بعد تجربة الشرق الأدنى القديم في إستكناهه أسطوريا وإستنطاقه بلغة النبوءة والشعر. يعنى هذا الكتاب بإستعراض التطور التاريخي للفلسفة في العالم الناطق باليونانية منذ بداياتها الأولى في الجزر الأيونية وإيطاليا، ومرورا باللحظة السقراطية وما أودعته فلسفتها لدى أفلاطون وأرسطو، لينتهي بآخر قمة فلسفية كتب باللاتينية، وهو القديس أوغسطين الذي عاش الجزء الأكبر من حياته في عنابة في الجزائر.
Book
Constructing a comprehensive disaster resilience index: The case of Italy
Measuring disaster resilience is a key component of successful disaster risk management and climate change adaptation. Quantitative, indicator-based assessments are typically applied to evaluate resilience by combining various indicators of performance into a single composite index. Building upon extensive research on social vulnerability and coping/adaptive capacity, we first develop an original, comprehensive disaster resilience index (CDRI) at municipal level across Italy, to support the implementation of the Sendai Framework for Disaster Risk Reduction 2015-2030. As next, we perform extensive sensitivity and robustness analysis to assess how various methodological choices, especially the normalisation and aggregation methods applied, influence the ensuing rankings. The results show patterns of social vulnerability and resilience with sizeable variability across the northern and southern regions. We propose several statistical methods to allow decision makers to explore the territorial, social and economic disparities, and choose aggregation methods best suitable for the various policy purposes. These methods are based on linear and non-liner normalization approaches combining the OWA and LSP aggregators. Robust resilience rankings are determined by relative dominance across multiple methods. The dominance measures can be used as a decision-making benchmark for climate change adaptation and disaster risk management strategies and plans.
Journal Article
Poverty and morality : religious and secular perspectives
\"This multi-authored book explores the ways that many influential ethical traditions - secular and religious, Western and non-Western - wrestle with the moral dimensions of poverty and the needs of the poor. These traditions include Buddhism, Christianity, Confucianism, Hinduism, Islam, and Judaism, among the religious perspectives; classical liberalism, feminism, liberal-egalitarianism, and Marxism, among the secular; and natural law, which might be claimed by both. The basic questions addressed by each of these traditions are linked to several overarching themes: what poverty is, the particular vulnerabilities of high-risk groups, responsibility for the occurrence of poverty, preferred remedies, how responsibility for its alleviation is distributed, and priorities in the delivery of assistance. This volume features an introduction to the types, scope, and causes of poverty in the modern world and concludes with Michael Walzer's broadly conceived commentary, which provides a direct comparison of the presented views and makes suggestions for further study and policy\"-- Provided by publisher.
Book
Exploring global changes in nitrogen and phosphorus cycles in agriculture induced by livestock production over the 1900–2050 period
Crop-livestock production systems are the largest cause of human alteration of the global nitrogen (N) and phosphorus (P) cycles. Our comprehensive spatially explicit inventory of N and P budgets in livestock and crop production systems shows that in the beginning of the 20th century, nutrient budgets were either balanced or surpluses were small; between 1900 and 1950, global soil N surplus almost doubled to 36 trillion grams (Tg)·y −1 and P surplus increased by a factor of 8 to 2 Tg·y −1 . Between 1950 and 2000, the global surplus increased to 138 Tg·y −1 of N and 11 Tg·y −1 of P. Most surplus N is an environmental loss; surplus P is lost by runoff or accumulates as residual soil P. The International Assessment of Agricultural Knowledge, Science, and Technology for Development scenario portrays a world with a further increasing global crop (+82% for 2000–2050) and livestock production (+115%); despite rapidly increasing recovery in crop (+35% N recovery and +6% P recovery) and livestock (+35% N and P recovery) production, global nutrient surpluses continue to increase (+23% N and +54% P), and in this period, surpluses also increase in Africa (+49% N and +236% P) and Latin America (+75% N and +120% P). Alternative management of livestock production systems shows that combinations of intensification, better integration of animal manure in crop production, and matching N and P supply to livestock requirements can effectively reduce nutrient flows. A shift in human diets, with poultry or pork replacing beef, can reduce nutrient flows in countries with intensive ruminant production.
Journal Article