Pretty happy to share this work on RNA polymerase II! We had a lot of fun studying this seemingly quite fundamental component of the system controlling Pol II levels & transcription. Amazing to get to work closely with Ana's group on this, combining imaging with genomics.

fascinating and ambitious work. @tobinatthelab Do you have any further data on the apparent selectivity over M2/3? It would be good to see HTL9936 tested in an additional assay to pERK, tested for antagonism, or some competition affinity measurements.

This is only becoming more important as more of us are pushed into casual or precarious employment. Big companies like USYD will exploit you if you let them.

Reminder to join your union wherever ever you work. There’s a lot that is crook about modern unis but pressure from organised labour protects workers. I am one (hopefully of many) beneficiary of this campaign against historical underpayment.

The precise role of MOR phosphorylation, and βarrestin recruitment, in this is an interesting outstanding question. More critically, it is unclear to what extent tolerance and withdrawal signs relate to 'addictive liability' of certain ligands.

As we discuss in our commentary, there is clearly a complex and yet to be understood series of mechanisms leading to both opioid tolerance and somatic withdrawal. https://t.co/ayi5iyw6At

In any case, recent experiments on the βarr2 KO, as well as the 11S/T-A phosphomutant MOR mice, make it clear that MOR/βarr2 KO interactions are not critical to OIRD. Additionally, there are now two separate publications showing morphine tolerance persists in βarr2 KO.

This complicates matters, as it is not trivial to compare recent experiments to those performed in the past in the situation where the genetic background of “129” animals, or an embryonic stem cell line, is unclear. https://t.co/9i8b56fqms

One interesting element I had not previously appreciated until writing my thesis was the historical problems with the 129 strains, and specifically the contaminated 129/SvJ strain. There is some excellent basic genetics work on this, for example: https://t.co/ZcnrR2vcTR

For example, this work from the Mogil group and others. https://t.co/oOt5bHUOEJ https://t.co/IL54iBo5aQ https://t.co/C1goePgtAz

There is literature on strain differences in terms of opioid effects, showing a lack of morphine tolerance in 129 substrains, and enhanced potency when compared to C57BL/6J. This suggests strain characteristics may have similarly confounded experiments on mixed-background animals

He et al. additionally show no effect of βarr2 KO on morphine potency or tolerance, the second publication to do so after the below work of Koblish et al. (see supps). These results are in also contrast to the initial publications on βarr2 KO animals. https://t.co/nJjmrNwBve

Parental strain (in this case 129) characteristics substantially contaminate experiments on mixed background (129xC57BL/6) knock-out animals. Recent βarr2 KO knock-out experiments have been performed on animals congenic with the C57BL/6J strain, where this confound is not present

This adds to other solid recent work showing substantial variation across mouse strains in terms of OIRD. These strain differences represent a confounding variable relevant to earlier experiments on βarr2 KO animals that showed a genotype effect on OIRD. https://t.co/m0DjXE54fB

He et al also show an effect of mouse strain (C57BL/6J vs 129/SvJ) on OIRD. Many reviews have been written on the role of strain background in transgenic mouse studies, specifically giving rise to false positives, such as this from Gerlai (in 1996!) https://t.co/yCVHznXDDg

https://t.co/NXITKtxZyq https://t.co/XWHEurpo3N https://t.co/fSxw716rCd

This paper is the fourth publication, representing the work of six discrete labs, to observe persistent, unchanged opioid-induced respiratory depression (OIRD) in βarrestin2 knock-out mice (an observation with large implications for opioid drug research).

With the publication of this interesting paper (and our associated commentary), I thought I would go through some elements of the broader discussion to highlight some work we were unable to cite. https://t.co/VLhB54rGbO

Racism and other preconceived prejudices have always and continue to influence biology. Disingenuous interpretations of biology continue to be used in many horrible ways.

“When I asked him how I should write about his life, he pulled out of his desk a list of every graduate student, postdoc and visitor at his laboratory” We should all look up to someone who saw the politics in science and the science in politics. https://t.co/tBvUc4rw7R