How the stability of the West Antarctic Ice Sheet has changed over the last 1.4 million years

March 12, 2016 in Articles 2015-16

Introduction

The West Antarctic Ice Sheet (WAIS) is part of the continental ice sheet which covers West Antarctic, the portion of Antarctica on the side of the Transantarctic Mountains which resides in the western hemisphere. The WAIS is residing on an archipelago with the center of the dome set over sub glacial uplands and bedrock basins, with the bedrock basins being more than 1,500 m below sea level. The WAIS contains 3.8 million km3 of ice, if this were ever to collapse and fall into the ocean, at the present rate of accumulation, it would take over ten thousand years for the ice to be restored. For around four decades there have been fears that there could be marine instability, fears caused by the retreat of the ice margin into basins which would lead to massive ice-mass loss and increased ice-calving, which would then result in the loss of the WAIS, resulting in a rapid-rise in sea level of 3-5 m.

A study recently published on the stability of the WAIS divide over the last 1.4 million years gives reason to believe that the divide of the WAIS has fluctuated only modestly in location and thickness for that amount of time.

Location, current status and studies

The Heritage Range which lies in the center of the Weddell Sea embayment is within 50 km of the floating Filchner-Ronne Ice Shelf and the grounded ice sheet in the Hercules Inlet. Two massifs are summits which cover 15 km of upland bounded by troughs excavated to below sea level. Ice from the central WAIS flows between and around the two mountains at the grounding line. The WAIS divide forms a large saddle (highest point between two massifs) between the main dome 300 km to the west, and to another 200 km northwest. Katabatic winds flow down the ice slope from the divide towards Hercules Inlet crossing the mountains and creating blue-ice areas. The winds cause the surface ice to melt which then causes an upward flow of ice which brings basal debris to the surface as blue-ice moraines. This ice-marginal, basally derived material is deposited higher on the mountain flanks and records past changes in ice thickness.

By using cosmogenic nuclide dating on the bedrock and nunataks (exposed, rocky ridges) data had been provided of the thickness of ice over time. A plethora of data was provided revealing data from ages of up to 400 ka. This lead the researchers to the hypothesis that the spread in ages represented the continuous presence of an ice sheet that fluctuated in thickness in response to glacial to interglacial cycles. The range of ages gives rise to preservation of some erratics (rocks alien to the locale) and deposition of other ice sheets during successive glaciations.

topography of antarctica

Subglacial topography of Antarctica showing the location of the WAIS in the Ellsworth mountains and geographical features within the Weddell sea.

What is gained from this study in particular

This helps in determining the stability of the WAIS as a combination of cosmogenic nuclide dating and geomorphological analysis of landforms can provide insight into the history of the ice-sheet. The advantage of using multiple nuclides in sampling is that the age and exposure can be found. Hein, A. S.  et al explains this;
For example, if a previously exposed clast is buried by ice long enough for the shorter lived of two nuclides to decay preferentially, the signal will be observed in the isotopic ratio. In the case of cosmogenic 26Al/10Be, it takes several tens of thousands of years for the burial signal to become evident. By measuring multiple isotopes in three adjacent erratics at each specific sampling site, the degree of scatter and extent to which the erratics have shared the same history of exposure can be determined. Thus, one can gain information on the age of deposition and possible subsequent overriding and disturbance by ice.”

The data from the study shows that the highest erratics are exposed for the longest time, and lower erratics are exposed for increasingly shorter times, this gives evidence of increased burial with decrease altitude. The implications of exposure ages of up to 1.4Ma at high elevations is that ice thickening and blue-ice moraine formation also occurred during earlier glacial cycles in the Pleistocene epoch. Due to mountains being seated near the grounding line of today, an increase in ice thickness near the mountains would agree with any seaward migration of the grounding line as ocean temperature cooled and global sea level fell. Over exposed periods of time you would expect glacial erosion to decrease ice-sheet surface in accordance with the mountains, triggering a cycle in changes of ice thickness superimposing a trajectory of lowering relative to the mountains. This is consistent with history.

It was argued that there were exposure periods of where the WAIS divide had adequate intervals of time to disappear, if it was to disappear then ice caps and glaciers would likely have built upon mountain massifs in a fjord landscape, however there is was evidence supporting this, instead pointed towards the continuous presence of an ice sheet in the southern sector of WAIS for the entire duration of 1.4Ma, this ice sheet adjusted to accommodate to the loss of marine-based portions of the WAIS during the interglacial periods, the intervals where the divide could have disappeared. This ice sheet has continued to stabilise the WAIS divide for over 1.4Ma and can be predicted to do so in the future as it gives no indication of loss in stability.

 

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by Jacqui

Can we edit GABRA3 to suppress AKT activation and therefore metastasis in breast cancer?

March 11, 2016 in Uncategorized

Around 58,000 women and men are diagnosed with breast cancer each year in the UK and out of this 11,500 dying from this disease. With the rate of breast cancer increasing by 3.5% a year it’s never been more important to find a way of reducing these statistics.

Why is Gabra3 important?

This study on Gabra3 suppression looks into identifying the processes in which metastasis occurs and ways to reduce it.

GABAa is an inhibitory neurotransmitter in the brain that acts as a channel in response chemicals binding. This study focused on GABAa receptor alpha 3 or Gabara3 normally found in the brain however has been found in metastatic breast cancer. This receptor is thought to kick start the AKT pathway.  It’s this pathway that stimulates cell migration and therefore metastasis.

Metastasis is a secondary tumour away from the initial site, and is the cause of most breast cancer fatalities. Which is why finding a way to reduce metastasis is important as this will reduce the ever increasing death toll.

Studying GABRA3 is vital as it’s only found in metastatic cancer tissues and as it’s a cell surface molecule has the potential to be a biochemical target. Currently being used to treat hypersomnia and therefore has the FDA approval making it more economically viable.

Experimenting with Gabra3

Cells expressing Gabra3 found in the MCF-7 cell line showed an increase in cell migration. To measure this MCF-7 cells were tagged with a biochemical marker and inserted into mice mammary fat pads.

mice 2

Shows the primary tumour and lung metastasis in mice shown using a Xenogen bioluminescence technique.

Mice that had the MCF-7 GABRA3 gene all developed lung metastasis as a result whereas the control mice showed no metastasis. This confirms that Gabra3 is having a significant effect and results in metastasis.

By altering the MDA-MB-436 breast cancer cells that express Gabra3 with the addition shRNA, which is a short RNS sequence that has a kink in it. This is used to silence target genes, this edited MDA-MB-436 Gabra3 shRNA should suppress Gabra3 and top the AKT pathway.

This edited gene was tested using mice again as the MDA-MB-436 that expressed the edited MDA-MB-436 shRNA and a control shRNA was inserted into the mammary fat pads.

mice 2

Shows the lung metastasis in the edited MDA-MB-436 shRNA and the control, shown using a Xenogen bioluminescence technique.

The results of this experiment show that 90% of the mice with the control shRNA developed lung metastasis. Whereas the mice with the shRNA edition only 29% developed lung metastasis. This shows that the edited MDA-MB-436 cells reduces the expression of Gabra3 reducing metastasis and increases survivability. Exactly how the shRNA edition suppresses the effects of Gabra3 is unknown and requires further experimentation.

But the body created has its own edition of Gabra3 that stops the AKT pathway activation. At the I/M site in the brain the Gabra3 undergoes A-to-I RNA Gabar3 edition. Unfortunately this edition only occurs in non-invasive (or primary) breast cancers and not in the metastatic cancer, however understanding how this edition occurs could be used to produce a potential drug.

 

By examining the differences between the non-invasive and metastatic breast cancer cells it was found that two specific enzymes operate this edition. These are ADAR1 and ADAR2 but its ADAR1 that is most significant.

ADAR1 generates the ADAR1p110 enzyme, this enzyme was found in the breast cancer cells along with the normal human epithelial cell line (HMEL). Whereas the other ADAR1 enzyme ADAR1p150 and ADAR2 were not found in the cell lines. This indicates that it’s the ADAR1p110 enzyme that causes the A-to-I Gabra3 edition.

To understand the effect of the A-to-I Gabra3 edition RNA edited Gabra3 with an A-to-G mutation was inserted to the I/M site in MDA-MB-436 cells in vitro expressing the unedited Gabra3. Cell migration and therefore metastasis was considerably reduced.

Leading from this the A-to-I edited Gabra3 was tested in vivo to see if it had similar affects as the in vitro experiment. Tagged MDA-MB-436 cells expressing the A-to-I edition plus a control were injected into mice.

Metastasis in mice 3

A-to-I edited Gabra3 and control injected into mice, shown using a Xenogen bioluminescence technique.

From this you can see that the control shows a high aggregation on metastatic cells, compared to the edited Gabra3 which shows a considerable difference in metastasis proving that the A-to-I edited Gabra3 has a positive effect in reducing metastasis.

The edited edition of Gabra3 works because the unedited Gabra3 is a cell surface molecule and the A-to-I edited Gabra3 decreases the expression of the Gabra3 therefore reduces the activation of the AKT pathway so cell migration reduced.

Edited and unedited Gabra3 were in vivo tested in MDA-MB-436 cell line to look at the interaction between the two Gabra3 molecules. They were added in an equal 1:1 ratio, the results of this show that the edited Gabra3 has the ability to suppress AKT pathway activation as a result of the unedited Gabra3 by 50%.

How Gabra3 causes metastasis is unknown, it’s been proven to activate the AKT pathway causing series of chain reactions that leads to cell migration. Stem cells are believed to contribute extensively to metastasis, Gabra3 increases this stem cell production. By observing the stem cell population with the addition of the edited Gabra3 it showed that the edited Gabra3 actually has no effect on stem cell populations. This also confirms that it is the unedited Gabra3 causing a substantial increase in stem cell population.

Future importance

Patient fatality due to breast cancer is either therapy resistance or the development of metastasis. That’s why this study is so important with options to either target Gabra3 specifically using shRNA or increasing the A-to-I edited Gabra3 production.

As Gabra3 is already a tried and tested molecule it already has FDA approval increasing its viability. In addition with this new evidence showing that Gabra3 has a significant importance and effect on cell migration and metastatic development further testing and experimentation on Gabra3 holds the solution to reducing patient fatalities caused by breast cancer.