Effets directs et aigus de médicaments insulinosensibilisateurs sur la cellule bêta des îlots pancréatiques : de l’outil de recherche à l’identification de la décélération métabolique comme mode d’action

Le diabète de type 2 (DT2) apparaît lorsque la sécrétion d’insuline par les cellules β des îlots du pancréas ne parvient plus à compenser la résistance à l’insuline des organes cibles. Parmi les médicaments disponibles pour traiter le DT2, deux classes agissent en améliorant la sensibilité à l’insuline : les biguanides (metformine) et les thiazolidinediones (pioglitazone et rosiglitazone). Des études suggèrent que ces médicaments protègent également la fonction des cellules β. Dans le but d’identifier des mécanismes par lesquels les médicaments insulinosensibilisateurs protègent les cellules β, nous avons étudié les effets aigus de la metformine et de la pioglitazone sur le métabolisme et la fonction des cellules INS 832/13, sécrétrices d’insuline et des îlots pancréatiques isolés de rats. Nous avons aussi validé in vivo avec des rats Wistar les principales observations obtenues en présence de pioglitazone grâce à des clamps glucidiques et par calorimétrie indirecte. Le traitement aigu des cellules β avec de la pioglitazone ou de la metformine inhibe la sécrétion d’insuline induite par le glucose en diminuant la sensibilité des cellules au glucose (inhibition en présence de concentrations intermédiaires de glucose seulement). Dans les mêmes conditions, les traitements inhibent aussi plusieurs paramètres du métabolisme mitochondrial des nutriments et, pour la pioglitazone, du métabolisme des lipides. Les composés affectent le métabolisme en suivant un patron d’inhibition similaire à celui observé pour la sécrétion d’insuline, que nous avons nommé « décélération métabolique ». La capacité de la pioglitazone à inhiber la sécrétion d’insuline et à ralentir le métabolisme mitochondrial de façon aigüe se confirme in vivo. En conclusion, nous avons identifié la décélération métabolique de la cellule β comme nouveau mode d’action pour les médicaments insulinosensibilisateurs. La décélération métabolique causée par les agents insulinosensibilisateurs les plus utilisés semble provenir d’une inhibition du métabolisme mitochondrial et pourrait être impliquée dans les bienfaits de ceux-ci dans un contexte de stress métabolique. Le fait que les deux agents insulinosensibilisateurs étudiés agissent à la fois sur la sensibilité à l’insuline et sur la sécrétion d’insuline, les deux composantes majeures du DT2, pourrait expliquer pourquoi ils sont parmi les agents antidiabétiques les plus efficaces. La décélération métabolique est une approche thérapeutique à considérer pour le traitement du DT2 et d’autres maladies métaboliques.

Efectos del tratado de libre comercio con los Estados Unidos en el sub sector arrocero Colombiano

El TLC se presenta como una gama de oportunidades para expandir la economía y generar crecimiento de la misma, Colombia debería realizar en materia de agricultura, más específicamente en el sub sector arrocero, un proceso por etapas y programado, evaluando las diferentes amenazas que podrían presentársele en el camino. Ahora bien, teniendo en cuenta que dicho tratado ya fue firmado y puesto en marcha, se debería entonces revisar sus efectos inmediatos en dónde se pueden corregir errores y vacíos ya generados por el mismo. Teniendo en cuenta que el Tratado de Libre Comercio con los Estados Unidos, si bien representa para Colombia una serie de inmensas posibilidades de crecimiento, también supone una serie de amenazas y aspectos que probablemente el país no esté en capacidad de afrontar en esta instancia, especialmente en el sector de la agricultura. En lo relacionado puntualmente con el sector del agro, se debería realizar un análisis más minucioso y no apostar todos los recursos a un mismo ítem, de manera tal que Colombia pueda tener, de ser necesario, la posibilidad de manejar alternativas de salida ante complejidades en el tratado (específicamente en lo relacionado con el agro) y así presentar menos riesgos al respecto. En el documento, se tratarán entonces aquellos criterios relacionados con estos temas, haciendo hincapié en la importancia que ha tenido para el sub sector arrocero el TLC, analizando aspectos favorables y desfavorables, centrándose en aspectos tecnológicos, estudiando lo que se puede corregir en el camino para trabajar y mejorar en este sub sector y de la misma forma para fortalecer los que se encuentran débiles y hacer aún más robustos aquellos que ya tienen beneficios de dicho TLC.​

Changes to Indian Ocean subantarctic mode water in a coupled climate model as CO2 forcing increases

Subantarctic mode water (SAMW) has been shown to be a good indicator of anthropogenic climate change in coupled climate models. SAMW in a coupled climate model and the response of modeled SAMW to increasing CO2 are examined in detail. How SAMW adjusts from climatological values toward a new equilibrium in the coupled model, with different climatological temperature and salinity properties, is shown. The combined formation rate of SAMW and Antarctic intermediate water is calculated as approximately 18 Sv (Sv ≡ 106 m3 s−1) in the Indian sector of the Southern Ocean, slightly lower than climatological values would suggest. When forced with increasing CO2, SAMW is produced at a similar rate but at lower densities. This result suggests that the rate of heat uptake in this part of the ocean will be unchanged by anthropogenic forcing. The important signal in the response of SAMW is the shift to colder and fresher values on isopycnals that is believed to be related to changes in thermodynamic surface forcing. It is shown that, given uniform forcing, SAMW is expected to enhance the signal relative to other water masses. Independent increases in surface heating or freshwater forcing can produce changes similar to those observed, but the two different types of forcing are distinguishable using separate forcing experiments, hodographs, and passive anomaly tracers. The changes in SAMW forced by increasing CO2 are dominated by surface heating, but changes to freshwater fluxes are also important.

A mechanism for the effect of tropospheric jet structure on the annular mode-like response to stratospheric forcing

For many climate forcings the dominant response of the extratropical circulation is a latitudinal shift of the tropospheric mid-latitude jets. The magnitude of this response appears to depend on climatological jet latitude in general circulation models (GCMs): lower latitude jets exhibit a larger shift. The reason for this latitude dependence is investigated for a particular forcing, heating of the equatorial stratosphere, which shifts the jet poleward. Spin-up ensembles with a simplified GCM are used to examine the evolution of the response for five different jet structures. These differ in the latitude of the eddy-driven jet, but have similar sub-tropical zonal winds. It is found that lower latitude jets exhibit a larger response due to stronger tropospheric eddy-mean flow feedbacks. A dominant feedback responsible for enhancing the poleward shift is an enhanced equatorward refraction of the eddies, resulting in an increased momentum flux, poleward of the low latitude critical line. The sensitivity of feedback strength to jet structure is associated with differences in the coherence of this behaviour across the spectrum of eddy phase speeds. In the configurations used, the higher latitude jets have a wider range of critical latitude locations. This reduces the coherence of the momentum flux anomalies associated with different phase speeds, with low phase speeds opposing the effect of high phase speeds. This suggests that, for a given sub-tropical zonal wind strength, the latitude of the eddy driven jet affects the feedback through its influence on the width of the region of westerly winds and the range of critical latitudes on the equatorward flank of the jet.

Sub-surface terahertz imaging through uneven surfaces: visualizing Neolithic wall paintings in Çatalhöyük

Pulsed terahertz imaging is being developed as a technique to image obscured mural paintings. Due to significant advances in terahertz technology, portable systems are now capable of operating in unregulated environments and this has prompted their use on archaeological excavations. August 2011 saw the first use of pulsed terahertz imaging at the archaeological site of Çatalhöyük, Turkey, where mural paintings dating from the Neolithic period are continuously being uncovered by archaeologists. In these particular paintings the paint is applied onto an uneven surface, and then covered by an equally uneven surface. Traditional terahertz data analysis has proven unsuccessful at sub-surface imaging of these paintings due to the effect of these uneven surfaces. For the first time, an image processing technique is presented, based around Gaussian beam-mode coupling, which enables the visualization of the obscured painting.

Southern annular mode dynamics in observations and models, Part I: The influence of climatological zonal wind biases in a comprehensive GCM

A common bias among global climate models (GCMs) is that they exhibit tropospheric southern annular mode (SAM) variability that is much too persistent in the Southern Hemisphere (SH) summertime. This is of concern for the ability to accurately predict future SH circulation changes, so it is important that it be understood and alleviated. In this two-part study, specifically targeted experiments with the Canadian Middle Atmosphere Model (CMAM) are used to improve understanding of the enhanced summertime SAM persistence. Given the ubiquity of this bias among comprehensive GCMs, it is likely that the results will be relevant for other climate models. Here, in Part I, the influence of climatological circulation biases on SAM variability is assessed, with a particular focus on two common biases that could enhance summertime SAM persistence: the too-late breakdown of the Antarctic stratospheric vortex and the equatorward bias in the SH tropospheric midlatitude jet. Four simulations are used to investigate the role of each of these biases in CMAM. Nudging and bias correcting procedures are used to systematically remove zonal-mean stratospheric variability and/or remove climatological zonal wind biases. The SAM time-scale bias is not alleviated by improving either the timing of the stratospheric vortex breakdown or the climatological jet structure. Even in the absence of stratospheric variability and with an improved climatological circulation, the model time scales are biased long. This points toward a bias in internal tropospheric dynamics that is not caused by the tropospheric jet structure bias. The underlying cause of this is examined in more detail in Part II of this study.

The ocean's role in polar climate change: asymmetric Arctic and Antarctic responses to greenhouse gas and ozone forcing

In recent decades, the Arctic has been warming and sea ice disappearing. By contrast, the Southern Ocean around Antarctica has been (mainly) cooling and sea-ice extent growing. We argue here that interhemispheric asymmetries in the mean ocean circulation, with sinking in the northern North Atlantic and upwelling around Antarctica, strongly influence the sea-surface temperature (SST) response to anthropogenic greenhouse gas (GHG) forcing, accelerating warming in the Arctic while delaying it in the Antarctic. Furthermore, while the amplitude of GHG forcing has been similar at the poles, significant ozone depletion only occurs over Antarctica. We suggest that the initial response of SST around Antarctica to ozone depletion is one of cooling and only later adds to the GHG-induced warming trend as upwelling of sub-surface warm water associated with stronger surface westerlies impacts surface properties. We organize our discussion around ‘climate response functions’ (CRFs), i.e. the response of the climate to ‘step’ changes in anthropogenic forcing in which GHG and/or ozone-hole forcing is abruptly turned on and the transient response of the climate revealed and studied. Convolutions of known or postulated GHG and ozone-hole forcing functions with their respective CRFs then yield the transient forced SST response (implied by linear response theory), providing a context for discussion of the differing warming/cooling trends in the Arctic and Antarctic. We speculate that the period through which we are now passing may be one in which the delayed warming of SST associated with GHG forcing around Antarctica is largely cancelled by the cooling effects associated with the ozone hole. By mid-century, however, ozone-hole effects may instead be adding to GHG warming around Antarctica but with diminished amplitude as the ozone hole heals. The Arctic, meanwhile, responding to GHG forcing but in a manner amplified by ocean heat transport, may continue to warm at an accelerating rate.

Antarctic ocean and sea ice response to ozone depletion: a two timescale problem

The response of the Southern Ocean to a repeating seasonal cycle of ozone loss is studied in two coupled climate models and found to comprise both fast and slow processes. The fast response is similar to the inter-annual signature of the Southern Annular Mode (SAM) on Sea Surface Temperature (SST), on to which the ozone-hole forcing projects in the summer. It comprises enhanced northward Ekman drift inducing negative summertime SST anomalies around Antarctica, earlier sea ice freeze-up the following winter, and northward expansion of the sea ice edge year-round. The enhanced northward Ekman drift, however, results in upwelling of warm waters from below the mixed layer in the region of seasonal sea ice. With sustained bursts of westerly winds induced by ozone-hole depletion, this warming from below eventually dominates over the cooling from anomalous Ekman drift. The resulting slow-timescale response (years to decades) leads to warming of SSTs around Antarctica and ultimately a reduction in sea-ice cover year-round. This two-timescale behavior - rapid cooling followed by slow but persistent warming - is found in the two coupled models analysed, one with an idealized geometry, the other a complex global climate model with realistic geometry. Processes that control the timescale of the transition from cooling to warming, and their uncertainties are described. Finally we discuss the implications of our results for rationalizing previous studies of the effect of the ozone-hole on SST and sea-ice extent. %Interannual variability in the Southern Annular Mode (SAM) and sea ice covary such that an increase and southward shift in the surface westerlies (a positive phase of the SAM) coincides with a cooling of Sea Surface Temperature (SST) around 70-50$^\circ$S and an expansion of the sea ice cover, as seen in observations and models alike. Yet, in modeling studies, the Southern Ocean warms and sea ice extent decreases in response to sustained, multi-decadal positive SAM-like wind anomalies driven by 20th century ozone depletion. Why does the Southern Ocean appear to have disparate responses to SAM-like variability on interannual and multidecadal timescales? Here it is demonstrated that the response of the Southern Ocean to ozone depletion has a fast and a slow response. The fast response is similar to the interannual variability signature of the SAM. It is dominated by an enhanced northward Ekman drift, which transports heat northward and causes negative SST anomalies in summertime, earlier sea ice freeze-up the following winter, and northward expansion of the sea ice edge year round. The enhanced northward Ekman drift causes a region of Ekman divergence around 70-50$^\circ$S, which results in upwelling of warmer waters from below the mixed layer. With sustained westerly wind enhancement in that latitudinal band, the warming due to the anomalous upwelling of warm waters eventually dominates over the cooling from the anomalous Ekman drift. Hence, the slow response ultimately results in a positive SST anomaly and a reduction in the sea ice cover year round. We demonstrate this behavior in two models: one with an idealized geometry and another, more detailed, global climate model. However, the models disagree on the timescale of transition from the fast (cooling) to the slow (warming) response. Processes that controls this transition and their uncertainties are discussed.

The influence of sea ice dynamics on the climate sensitivity and memory to increased Antarctic sea ice

The study analyzes the sensitivity and memory of the Southern Hemisphere coupled climate system to increased Antarctic sea ice (ASI), taking into account the persistence of the sea ice maxima in the current climate. The mechanisms involved in restoring the climate balance under two sets of experiments, which differ in regard to their sea ice models, are discussed. The experiments are perturbed with extremes of ASI and integrated for 10 yr in a large 30-member ensemble. The results show that an ASI maximum is able to persist for ; 4 yr in the current climate, followed by a negative sea ice phase. The sea ice insulating effect during the positive phase reduces heat fluxes south of 60 8 S, while at the same time these are intensified at the sea ice edge. The increased air stability over the sea ice field strengthens the polar cell while the baroclinicity increases at midlatitudes. The mean sea level pressure is reduced (increased) over high latitudes (midlatitudes), typical of the southern annular mode (SAM) positive phase. The Southern Ocean (SO) becomes colder and fresher as the sea ice melts mainly through sea ice lateral melting, the consequence of which is an increase in the ocean stability by buoyancy and mixing changes. The climate sensitivity is triggered by the sea ice insulating process and the resulting freshwater pulse (fast response), while the climate equilibrium is restored by the heat stored in the SO subsurface layers (long response). It is concluded that the time needed for the ASI anomaly to be dissipated and/or melted is shortened by the sea ice dynamical processes.

Description of loxocythere (novoloxocythere) pelius subgen. sp. nov. (ostracoda) from the cenozoic of S.E. Australia with comments on species of antarctiloxoconcha hartmann, 1986 and loxoreticulatum benson, 1964 from Australian and Antarctic marine waters

Loxocythere (Novoloxocythere) pelius subgen. et sp. nov. is described from Upper Miocene strata of the Port Phillip and Western Port Basins. Victoria. It has its acme in shallow open marine facies of latest Miocene (Cheltenhamian) age. This species, along with Loxocythere (Novoloxocythere) kerryswansoni Yassini and Jones, 1995, forms a discrete group of rotund Australian Loxocythere species that possess posterior extremities in both valves that are positioned well above mid carapace height (i.e. adjacent to dorsal margin). This feature along with a sub-triangular inner margin outline, defines a carapace shape that is distinct from that of rotund species of Loxocythere (loxocythere) Hornibrook, 1952 and Antarctiloxoconcha Hartmann, 1986. The type species of Antarctiloxoconcha – A.frigida (Neale. 1967), possesses internal carapace features that are very similar to the type species of Loxocythere - L. crassa Hornibrook, 1952. Both have relatively short carapaces and sub-quadrate inner margin outlines with posterior extremities in both valves positioned below mid carapace height. Species of Loxocythere (Novoloxocythere), in particular L. (N.) kerryswansoni, have a carapace shape that is transitional between Loxocythere and Loxoreticulatum Benson, 1964. Species of Loxoreticulatum generally possess a sub-parallelogram shaped carapace/inner margin and arched median hinge element. The latter feature is distinct from the mostly straight median hinge elements of Loxocythere (Loxocythere) and Loxocythere (Novoloxocythere) species. Species of Loxocythere (Novoloxocythere) are also readily distinguishable from relatively elongate species of Loxocythere, such as L. (L.) hornibrooki McKenzie, 1967, as the latter possess long (for genus), sub-rectangular shaped carapaces/inner margin outlines and posterior extremities below mid height.

Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?

Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the  mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to ≤60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 μM arsenite (As^III) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase β and DNA ligase I. At higher concentrations (> 10 μM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.

The comparative energetics and growth strategies of sympatric Antarctic and subantarctic fur seal pups at Iles Crozet

The period of maternal dependence is a time during which mammalian infants must optimise both their growth and the development of behavioural skills in order to successfully meet the demands of independent living. The rate and duration of maternal provisioning, post-weaning food availability and climatic conditions are all factors likely to influence the growth strategies of infants. While numerous studies have documented differences in growth strategies at high taxonomic levels, few have investigated those of closely related species inhabiting similar environments. The present study examined the body composition, metabolism and indices of physiological development in pups of Antarctic fur seals (Arctocephalus gazella) and subantarctic fur seals (Arctocephalus tropicalis), congeneric species with different weaning ages (4 months and 10 months, respectively), during their overlap in lactation at a sympatric breeding site in the Iles Crozet. Body lipid reserves in pre-moult pups were significantly greater (t₂₈=2.73, P<0.01) in subantarctic (26%) than Antarctic fur seals (22%). Antarctic fur seal pups, however, had significantly higher (t₂₆=3.82, P<0.001) in-air resting metabolic rates (RMR; 17.1±0.6 ml O₂ kg^-1 min^-1) than subantarctic fur seal pups (14.1±0.5 ml O2 kg^-1 min^-1). While in-water standard metabolic rate (SMR; 22.9±2.5 ml O2 kg^-1 min^-1) was greater than in-air RMR for Antarctic fur seal pups (t₉=2.59, P<0.03), there were no significant differences between in-air RMR and in-water SMR for subantarctic fur seal pups (t₁₂=0.82, P>0.4), although this is unlikely to reflect a greater ability for pre-moult pups of the latter species to thermoregulate in water. Pup daily energy expenditure was also significantly greater (t₂₇=2.36, P<0.03) in Antarctic fur seals (638±33 kJ kg^-1 day^-1) than in subantarctic fur seals (533±33 kJ kg^-1 day^-1), which corroborates observations that pups of the former species spend considerably more time actively learning to swim and dive. Consistent with this observation is the finding that blood oxygen storage capacity was significantly greater (t₉=2.81, P<0.03) in Antarctic (11.5%) than subantarctic fur seal (8.9%) pups. These results suggest that, compared with subantarctic fur seals, Antarctic fur seal pups adopt a strategy of faster lean growth and physiological development, coupled with greater amounts of metabolically expensive behavioural activity, in order to acquire the necessary foraging skills in time for their younger weaning age.

Fasting metbabolism in Antarctic fur seal (Artocephalus gazella) pups

The metabolism of 52–73-day old Antarctic fur seal pups from Bird Island, South Georgia, was investigated during fasting periods of normal duration while their mothers were at sea foraging. Body mass decreased exponentially with pups losing 3.5–3.8% of body mass per day. Resting metabolic rate also decreased exponentially from 172–197 ml (O2)·min⁻¹ at the beginning of the fast and scaled to M_b^0.74 at 2.3 times the level predicted for adult terrestrial mammals of similar size. While there was no significant sex difference in RMR, female pups had significantly higher (F₁,₁₈=6.614, P<0.019) mass-specific RMR than male pups throughout the fasting period. Fasting FMR was also significantly (t₁₅=2.37, P<0.035) greater in females (823 kJ·kg⁻¹·d⁻¹) than males (686 kJ·kg⁻¹·d⁻¹). Average protein turnover during the study period was 19.3 g·d⁻¹ and contributed to 5.4% of total energy expenditure, indicating the adoption of a protein-sparing strategy with a reliance on primarily lipid catabolism for metabolic energy. This is supported by observed decreases in plasma BUN, U/C, glucose and triglyceride concentrations, and an increase in β-HBA concentration, indicating that Antarctic fur seals pups adopt this strategy within 2–3 days of fasting. Mean RQ also decreased from 0.77 to 0.72 within 3 days of fasting, further supporting a rapid commencement of protein-sparing. However, RQ gradually increased thereafter to 0.77, suggesting a resumption of protein catabolism which was not substantiated by changes in plasma metabolites. Female pups had higher TBL (%) than males for any given mass, which is consistent with previous findings in this and other fur seal species, and suggests sex differences in metabolic fuel use. The observed changes in plasma metabolites and protein turnover, however, do not support this.

Direct evidence of histopathological impacts of wastewater discharge on resident Antarctic fish (Trematomus bernacchii) at Davis Station, East Antarctica.

During the 2009/2010 summer, a comprehensive environmental impact assessment (EIA) of the wastewater discharge at Davis Station, East Antarctica was completed. As part of this, histological alteration of gill and liver tissue in Antarctic Rock-cod (Trematomus bernacchii) from four sites along a spatial gradient from the wastewater outfall were assessed. All fish within 800 m of the outfall exhibited significant histological changes in both tissues. Common pathologies observed in fish closest to the outfall include proliferation of epithelial cells with associated secondary lamellar fusion in the gills and multifocal granulomata with inflammation and necrosis as well as cysts in the liver. Fish from sites >800 m from the outfall also exhibited alterations but to a lesser degree, with prevalence and severity decreasing with increasing distance from the outfall. This study highlights the value of histopathological investigations as part of EIAs and provides the first evidence of sub-lethal alteration associated with wastewater discharge in East Antarctica.

Application of a quantitative histological health index for Antarctic rock cod (Trematomus bernacchii) from Davis Station, East Antarctica

A quantitative Histological Health Index (HHI) was applied to Antarctic rock cod (Trematomus bernacchii) using gill, liver, spleen, kidney and gonad to assess the impact of wastewater effluent from Davis Station, East Antarctica. A total of 120 fish were collected from 6 sites in the Prydz Bay region of East Antarctica at varying distances from the wastewater outfall. The HHI revealed a greater severity of alteration in fish at the wastewater outfall, which decreased stepwise with distance. Gill and liver displayed the greatest severity of alteration in fish occurring in close proximity to the wastewater outfall, showing severe and pronounced alteration respectively. Findings of the HHI add to a growing weight of evidence indicating that the current level of wastewater treatment at Davis Station is insufficient to prevent impact to the surrounding environment. The HHI for T. bernacchii developed in this study is recommended as a useful risk assessment tool for assessing in situ, sub-lethal impacts from station-derived contamination in coastal regions throughout Antarctica.