2,521 research outputs found
Rutter, Michael: transcript of a video interview (18-Dec-2006 and 15-Feb-2007)
No full textMichael Rutter is a leading international figure in academic psychiatry. He has worked in the USA, University of Birmingham and for much of his career at the Institute of Psychiatry in London. His research has included the epidemiology of childhood psychiatric illnesses, longitudinal studies of school effectiveness, depression and attention deficit hyperactivity disorder. He has written extensively about childhood autism, including autistic “idiots savants”. He is well known for studying the interplay of nature and nurture in the development of childhood psychiatric disturbances, and devised objective measurements of the “deprivation index” in a child’s environment, showing that this correlated with the risk of developing antisocial behaviour, drug taking or criminality.Supported by a Wellcome Trust Public Engagement grant (2006-2008) in the History of Medicine to Professor Tilli Tansey (QMUL) and Professor Leslie Iversen (Oxford), this project recorded interviews with 12 prominent neuroscientists, between 2006 and 2008
How Cells Choose To Create Energy
No full textTo supply their energy needs, cells typically choose between utilizing glucose in the cytoplasm (aerobic glycolysis and lactic acid fermentation) or "burning" pyruvate in the mitochondria (mitochondrial carbohydrate oxidation). Although this is arguably the most fundamental metabolic decision that cells must make, prior to 2012 it was not clear how cells import pyruvate into mitochondria to fuel ATP production. That year, Rutter, Thummel and colleagues identified the heterodimeric MPC1/MPC2 complex as the mitochondrial pyruvate carrier. Their paper also identified and explained the severe metabolic defects found in families with mpc1 gene mutations. Rutter and collaborators have subsequently shown that the choice of whether or not to import pyruvate has far-reaching medical implications because stem cells and most cancer cells are glycolytic (the "Warburg Effect"). They showed that this is often because cells down-regulate MPC expression, and that MPC re-expression reverses the Warburg Effect, impedes tumor growth, and drives cell differentiation. These discoveries have revolutionized our understanding of the role of metabolic decisions in determining cell state and fate
Biologically targeted probes for Zn2+: a diversity oriented modular “click-SNAr-click” approach
No full textWe describe a one-pot strategy for the high yielding, operationally simple synthesis of fluorescent probes for Zn2+ that bear biological targeting groups and exemplify the utility of our method through the preparation of a small library of sensors. Investigation of the fluorescence behaviour of our library revealed that although all behaved as expected in MeCN, under biologically relevant conditions in HEPES buffer, a plasma membrane targeting sensor displayed a dramatic switch on response to excess Zn2+ as a result of aggregation phenomena. Excitingly, in cellulo studies in mouse pancreatic islets demonstrated that this readily available sensor was indeed localised to the exterior of the plasma membrane and clearly responded to the Zn2+ co-released when the pancreatic beta cells were stimulated to release insulin. Conversely, sensors that target intracellular compartments were unaffected. These results demonstrate that this sensor has the potential to allow the real time study of insulin release from living cells and exemplifies the utility of our simple synthetic approac
MiR-184 expression is regulated by AMPK in pancreatic islets
No full textAMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β-cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits (βAMPKdKO mice) impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β-cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β-cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets
Integrating cytosolic calcium signals into mitochondrial metabolic responses.
No full textStimulation of hepatocytes with vasopressin evokes increases in cytosolic free Ca2+ ([Ca2+]c) that are relayed into the mitochondria, where the resulting mitochondrial Ca2+ ([Ca2+]m) increase regulates intramitochondrial Ca2+-sensitive targets. To understand how mitochondria integrate the [Ca2+]c signals into a final metabolic response, we stimulated hepatocytes with high vasopressin doses that generate a sustained increase in [Ca2+]c. This elicited a synchronous, single spike of [Ca2+]m and consequent NAD(P)H formation, which could be related to changes in the activity state of pyruvate dehydrogenase (PDH) measured in parallel. The vasopressin-induced [Ca2+]m spike evoked a transient increase in NAD(P)H that persisted longer than the [Ca2+]m increase. In contrast, PDH activity increased biphasically, with an initial rapid phase accompanying the rise in [Ca2+]m, followed by a sustained secondary activation phase associated with a decline in cellular ATP. The decline of NAD(P)H in the face of elevated PDH activity occurred as a result of respiratory chain activation, which was also manifest in a calcium-dependent increase in the membrane potential and pH gradient components of the proton motive force (PMF). This is the first direct demonstration that Ca2+-mobilizing hormones increase the PMF in intact cells. Thus, Ca2+ plays an important role in signal transduction from cytosol to mitochondria, with a single [Ca2+]m spike evoking a complex series of changes to activate mitochondrial oxidative metabolism
Monitoramento e modelagem do processo de interceptação da chuva de uma bacia coberta por floresta ombrófila mista
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Ambiental, Florianópolis, 2015.A interceptação é o processo pelo qual a precipitação que cai sobre a superfície do terreno fica retida, é redistribuída ao solo ou evapora posteriormente. Esse processo é importante especialmente em áreas florestais, pois influencia na reciclagem da umidade do ar e também na quantidade de água que efetivamente chega ao solo. A maioria dos estudos de interceptação nas florestas brasileiras foi feita na região Amazônica e Mata Atlântica, mas poucos foram os estudos realizados na Mata Atlântica do tipo Floresta Ombrófila Mista. O objetivo deste trabalho foi compreender e estimar os processos de interceptação da chuva em uma bacia coberta por Floresta Ombrófila Mista por meio de monitoramento e modelagem. A perda por interceptação (I) foi estimada por meio da medição de chuva externa (P), chuva interna (Tf) e escoamento pelo tronco (Sf). O monitoramento da chuva externa foi feito com três pluviômetros e um pluviógrafo instalados fora da bacia. Nove pluviômetros e uma calha interligada a um pluviógrafo foram instalados para o monitoramento da chuva interna. O monitoramento do escoamento pelo tronco foi realizado em dez árvores interligadas a um recipiente de armazenamento e mais quatro árvores interligadas a um pluviógrafo. Os índices de cobertura do dossel foram estimados a partir de fotografias do dossel. Os dados hidrometeorológicos foram monitorados na estação meteorológica do Rio Feio. A chuva externa nos três anos de monitoramento somou 5.309 mm distribuídos em 321 eventos e houve 489 dias sem ocorrência de chuva. Os modelos de Rutter esparso e de Gash esparso foram utilizados para a modelagem do processo de interceptação. A chuva interna variou de 61 a 83% da chuva externa, o que demonstrou que a chuva interna é heterogênea na bacia coberta por Floresta Ombrófila Mista. O volume de escoamento de tronco variou de 0,1 a 22,9 litros, com média de 2,92 litros e no período monitorado os volumes tenderam a crescer com o aumento do diâmetro do tronco e da área da copa. O índice de cobertura do dossel na bacia variou de 45 a 94%, com média de 80% e não apresentou correlação com a distribuição da chuva interna. Os dados automatizados da chuva interna e escoamento pelo tronco foram distribuídos em 60 eventos, a chuva externa foi 1.303 mm, a chuva interna e escoamento pelo tronco corresponderam a 75% (981 mm) e 2 % (19 mm) da chuva externa. A média da evapotranspiração potencial da série calculada foi de 1,09 mm dia-1. O erro relativo por evento dos modelos de interceptação variou de 2 a 400% para o modelo de Rutter e de 0 a 350% para o modelo de Gash. O modelo de Gash subestimou a I acumulada enquanto que o modelo de Rutter a superestimou. A simulação com o modelo de Rutter foi a que obteve os menores valores do erro relativo (4%) em relação a I acumulada. Os dois modelos tiveram limitações para representar o processo de interceptação em eventos extremos, possivelmente devido aos erros associados à estrutura dos modelos assim como ao conjunto de dados medidos e estimados.Abstract :The interception is the process by which the precipitation that falls on the ground surface is retained, it is redistributed to the ground or evaporate later. This process is important especially in forested areas since it influences recycling of moisture from the air and also the amount of water that effectively reaches the ground. Most of the interception studies in Brazilian Forests were carried out in the Amazon and Atlantic Forest, but few have been conducted in the Atlantic Forest Mixed Ombrophilous Forest type. The objective of this work was to understand and estimate the process of interception of rain in an experimental catchment covered by Mixed Ombrophilous Forest through monitoring and modeling. The interception loss will be estimated by measuring rainfall (P), throughfall (Tf) and stemflow (Sf). The monitoring consists of three rain gauges and automatic rain gauge installed outside the basin for rainfall monitoring. Nine gauges and one trough-type collectors coupled to a rain gauge for throughfall monitoring. The stemflow monitoring was conducted in ten trees connected to a storage container and four trees connected to a rain gauge. The canopy cover fraction was estimated using photographs taken of the canopy. Hydrometeorological data were acquired with a meteorological station of Rio Feio. The Rutter and Gash models were used to model the interception process. The total rainfall monitoring of the complete 3 years was 5.309 mm, from 321 rainfall events and in 489 days there was no rainfall. The throughfall ranged from 61 to 83% the rainfall, which showed the throughfall heterogeneity. The stemflow ranged from 0,1 to 22,9 liters, averaging 2,92 liters and the volumes tend to increase with the diameters at breast height and crown area increases. The canopy cover fraction ranged from 45 to 94 %, averaging 80%. The calculation of the interception loss using automated date rail and stemflow were distributed in 60 events. The rainfall (P) was 1303 mm, Tf and Sf corresponded to 75% (981 mm) and 2% (19 mm) of P. The mean potential evapotranspiration was 1.09 mm day-1. The relative error in the models for the events ranged from 2 to 400% for the Rutter model and 0 to 350% for the Gash model. The Gash model underestimated I while the simulation of the Rutter model overestimated. The simulation with the Rutter model was the one with the lowest values of relative error (4%) for I accumulated. Both models have limitations to identify the process of interception
Specificity and heterogeneity in children's responses to profound institutional privation.
No full textBackground The sequelae of profound early privation are varied.Aims To delineate the behavioural patterns that are specifically associated with institutional privation.Method A group of 165 children adopted from Romania before the age of 42 months were compared at 4 years and 6 years with 52 non-deprived UK children adopted in infancy. Dysfunction was assessed for seven domains of functioning. The groups were compared on which, and how many, domains were impaired.Results Attachment problems, inattention/overactivity, quasi-autistic features and cognitive impairment were associated with institutional privation, but emotional difficulties, poor peer relationships and conduct problems were not. Nevertheless, one-fifth of children who spent the longest time in institutions showed normal functioning.Conclusions Attachment disorder behaviours, inattention/overactivity and quasi-autistic behaviour constitute institutional privation patterns
Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming
No full textIn recent years, mitochondria have emerged as important targets of agonist-dependent increases in cytosolic Ca(2+) concentration. Here, we analyzed the significance of Ca(2+) signals for the modulation of organelle function by directly measuring mitochondrial and cytosolic ATP levels ([ATP](m) and [ATP](c), respectively) with specifically targeted chimeras of the ATP-dependent photoprotein luciferase. In both HeLa cells and primary cultures of skeletal myotubes, stimulation with agonists evoking cytosolic and mitochondrial Ca(2+) signals caused increases in [ATP](m) and [ATP](c) that depended on two parameters: (i) the amplitude of the Ca(2+) rise in the mitochondrial matrix, and (ii) the availability of mitochondrial substrates. Moreover, the Ca(2+) elevation induced a long-lasting priming that persisted long after agonist washout and caused a major increase in [ATP](m) upon addition of oxidative substrates. These results demonstrate a direct role of mitochondrial Ca(2+) in driving ATP production and unravel a form of cellular memory that allows a prolonged metabolic activation in stimulated cells
Regulation of mitochondrial ATP syntesis by calcium: evidence for a long-term metabolic priming.
No full textIn recent years, mitochondria have emerged as important targets of agonist-dependent increases in cytosolic Ca(2+) concentration. Here, we analyzed the significance of Ca(2+) signals for the modulation of organelle function by directly measuring mitochondrial and cytosolic ATP levels ([ATP](m) and [ATP](c), respectively) with specifically targeted chimeras of the ATP-dependent photoprotein luciferase. In both HeLa cells and primary cultures of skeletal myotubes, stimulation with agonists evoking cytosolic and mitochondrial Ca(2+) signals caused increases in [ATP](m) and [ATP](c) that depended on two parameters: (i) the amplitude of the Ca(2+) rise in the mitochondrial matrix, and (ii) the availability of mitochondrial substrates. Moreover, the Ca(2+) elevation induced a long-lasting priming that persisted long after agonist washout and caused a major increase in [ATP](m) upon addition of oxidative substrates. These results demonstrate a direct role of mitochondrial Ca(2+) in driving ATP production and unravel a form of cellular memory that allows a prolonged metabolic activation in stimulated cells
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