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~Patrick's Wiki~

week 1 October 5 2017

I think these works by Tomasetti and Vogelstein introduce a better basis for paying attention to R, DNA replication errors, and that they may be more critical to watch rather than hereditary and environmental factors for many cancers

1. Is the expectation of endogenous mutations resulting from only stem cell divisions, would be the same among all human populations at any given age?

2. Is analysis of 2/3 of world population enough or do we require 80 or 90% to be considered comprehensive?

3. Design an experiment to test their hypothesis in the lab?

4. Think about cancer in a new light in regards to what causes cancer?

5. Is there an additional model to rule out environmental and hereditary influence on cancer rates?

week 2 October 10 2017 - Identifiers for the 21st Century

1. This paper describes very nicely why it is important to take data organization, preservation, and curation seriously.

2. As the next generation of scientists, it is on us to be part of the changing force for correct organization and curations.

3. The amount of reference rot was really high, approximately 20%.

4. Identifiers are only useful in context.

5. Machine learning is likely to be affected? It is only as good as the data to analyze.

6. Tombstone page is a really cool term.

~Discussion questions~

What powers do scientists have to help implement these improvements beyond practice?

The framework behind how published papers are currently maintained and managed is very complicated, do you think this should be something that all PhD students should be taught?

week 3 October 17 2017 - TZAP: telomere protein

1. The field had previously known that telomere length is important for long-term survival, but it was not known how telomeres can be shortened quickly. Telomere lengths should be "the right length;" not too short, not too long.

2. Are rat telomeres different? Is this true for all mammalian organisms (besides human and mice)?

3. Are sex differences in telomere lengths? hermaphrodites? identical twins?

4. Not familiar with these assays, would be nice to get more background on their methods.

5. I think this paper ultimately shows how important TZAP is for homeostasis.

week 4 October 24 2017 - Heterocrhomatin machinery

~Thoughts on paper~

-Transcription-repressing chromatin -PIWI-interacting RNA clusters piRNA -Moonshiner-paralogue of basal transcription factor IIA (TFIIA) -Rhino-heterochromatin protein-1 variant -transposons are virus-like genomic parasites -heterochromatin repress transcription of transposon DNA -Deadlock & Rhino together bind Moonshiner -Moonshiner binds to other proteins that are part of the typical transcription-initiation complex -Sense vs. anti-sense RNA -Transcription to occur without transcription -Very large complex! -Good methods

week 5 October 31 2017 - TADs affecting chromatin structure

-TADs are very important for enhancer promoter interactions

-TAD disruption is important for syndromes, at least hand development syndromes.

-Really neat to see that there are defined boundaries of genes that do not overlap and that the non-coding regions are important.

-We normally think of genes functioning in a linear way but this paper changes that paradigm.

-Figure 7 was the most helpful figure in the entire paper. Showing how the differences in Enhancer position leads to pathogenicity was very helpful.

-The mouse model recapitulating the human condition was really neat to see in this paper.

-Interesting to see what the translational implication will be from this work.

-CRISPR induced chromosome rearrangement?

week 6 November 7 2017 - Cohesin and Loop Domains of Chromatin

-I really liked the auxin-inducible degron, was a nice system to test their hypotheses.

-Contrasted with WAPL knockout was good data. I enjoyed thinking about removal of cohesin and over expression of cohesin and what their affects are.

-It also helped to think about loop domains/TADs and then pivot to purely histone modifications such as methylation and acetylation for boundaries rather than CTCF and cohesin.

-There must be some greater use of this flexibility for cell division and cell repair.

-Without loops/TADs there is still organization to the chromosomes which I would guess has meaning for evolution. However, cohesin and CTCF are still critical for proper use of the chromosomes, just a different kind of organization.

-This is a very detailed look at structure but what is the higher level effects on biology? Many papers we have read in Cell are not good at saying what this means for the bigger biological picture.

-What are these changes in the chromosome doing in the context of T cells? Cancer cells? Epithelial cells?

week 7 November 16 2017 - HSP70/HSP90 and Genetic Variation

Presenter 1

week 8 November 28 2017 - Competition of mitogen an p53 signaling controlling cell-cycle entry

Presenter 2

week 9 December 5 2017 - 5' UTR m6A promotes cap-independent translation

Very nice flow of the figures for supporting their claim.

Would like to hear more discussion of toeprinting assay. Sounds very useful in this context.

HeLa cell extracts were nicely used to demonstrate that m6A enables cap-independent translation. Good use of m7GppG for a control!

Figure 2 was my favorite figure. Easy to read and not dense. Convincing without the need of extra complexity seen in other papers.

Also really liked Figure 3. The addition of a hairpin at the 5' UTR was great, one of my favorite experiments in the paper.

Their biggest weakness with cell stress was only testing HSP70 presence to heat shock. Where are the data supporting eIF3 in heat shock conditions?

Where's HSP90?

Interesting that un-capped translation is available in eukaryotes; when do eukaryotes need this in response to cell stress? Already have HSPs to help correct mis-translations or other checkpoints to prevent cell cycle and other protective programs.

week 10 December 12 2017 - Nucleic acid detection with CRISPR-Cas13a/C2c2

This is a really cool paper. A nice way to go from the very detailed research of previous papers to a clinical and translation focused science paper. An really good example of how basic science is utilized to positively impact humanity in an accessible way.

Thinking about this paper for lower income regions made me think of, is qPCR cheap and easy to do in a rural/low income area? I suppose there may be old qPCR tools that are cheaply available to take advantage of SHERLOCK.

The sensitivity of SHERLOCK is pretty astonishing. That's like finding a needle in a haystack the size of Oregon.

I would like to ask about variation in the loop motif of the crRNA. Does it also require strict rules to have the correct loop to function in recognition of the target RNA.

The assay seems very straightforward. It also sounds like contamination shouldn't be an issue since the authors show discrimination off of SNPs at low concentrations.

The clinical promise is really compelling. The sensitivity could tell you that you have Dengue before you get the fevers for example.

      • I wonder if it could be used to Dx sepsis, which kills 500 people a day in the US. All ages. Hard to Dx and once people start getting sick it is often too late for effective intervention.