12/24/2018

Biopharma/Investing
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Stay market neutral! Stocks fall, too. 10 years of stocks rising has to get reversed at some point. “When the tide goes out, we see who has been swimming naked.”

Papers I’ve Read
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Mutations in TOP3a Cause a Bloom Syndrome-like Disorder. Martin et al. Am J Hum Genet 103, 2018.
The BTRR complex repairs double Holliday junctions. Without any of the BTRR members, this phenotype involving growth destriction, microcephaly and cancer predisposition is seen. TopoIIIalpha is a component of BTRR and these researchers identify 12 patients with TOP3A and RMI1 (another component of BTRR) mutations. It appears TOP3A homozygous LOF is incompatible with life (Li et al, PNAS 1998) and the authors speculate that these are severe hypomorphic alleles. I don’t see much of a therapeutic strategy here, perhaps gene therapy could reduce sister chromatid exchanges and other chromosomal abnormalities seen in this family of diseases, potentially reducing new onset neoplasms, but with no benefit towards dysmorphic symptoms.

Signalling Pathways and Cellular Mechanisms Regulating Mossy Fiber Sprouting in the Development of Epilepsy. Godale & Danzer. Front Neurol 2018.
As is my reaction to many neuroscience papers, I’m more confused on the subject matter after reading this one.

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Liu et al. Hum Mol Genet 2018.
I didn’t know much about the T-box transcription factors going into this paper, so it was helpful to get acquainted with these powerful developmental regulators. DiGeorge syndrome is a somewhat well-known rare disease caused by TBX1 deletion, and it appears there are a slew of other T-box disorders, including now, TBX2 variants. TBX2 seems extremely sensitive to gene dosage, with heterozygote hypomorphs and duplication variants both causing disease. The workers here use similar tools to ones I’ve highlighted before including GeneMatcher and the Undiagnosed Diseases Network. Without giving away my own secrets, the bioinformatics tools used in this paper are comprehensive and impressive. The ortholog work is not–drosophila are clearly not the best species to test TBX variants. Anyway, with only 4 patients found (3 in one family), it’s a little hard to get excited about this work or even think about a therapeutic given the extreme gene dosage sensitivity and the developmental nature of the disorder.

Brief Book Review – The Big Con by David M. Maurer
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“A feast of language” boasts the front cover. Indeed, should you desire satiety from a diet of anachronistic cant, TBC will not disappoint. Maurer is a splendid writer outside of the confidence man’s argot, which is disappointingly dated. One cannot envision the last time someone took “a touch” off of the “rag”. Yet, it is still fun to get a glimpse of the early part of last century’s underworld dialect. With fascinating stories/examples of these touches (confidence games run to successful completion), Maurer keeps his work alive despite a fatally boring premise. In some subtextual senses, the book is about human nature and good vs. evil. But the dreary meta-premise is that perhaps the greedy victim, who Maurer posits is so blinded by cupidity that he is invariably willing to join in connivance with the confidence man (of course only to be fleeced at the end), is really the bad guy. Building sympathy for con artists is hard, and Maurer doesn’t intentionally do so, but his wry commentary and somewhat unbelievable access to this cohort of miscreants makes one wonder which side he’s on. The reality is he is just a linguistics enthusiast, so much so, he was willing to dive head-first into this unknown world to simply learn new usages. There is precious little technical discussion of semantics in the style of a, say, Chomsky. Maurer is just the real deal word guy, giving an incidental window of the lives of the con vernacular.

Clinical Trials I’ve Noticed
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Study of Potential for Drug Interactions Mediated by CYP3A4 Inhibition With Aramchol in Healthy Volunteers. Galmed Pharmaceuticals.
I had almost forgotten about bile acids since I had built Retrophin’s bile acid business in 2014 (which should be going generic soon, by the way). Galmed has a cholic acid combination product I was a bit worried about. Not sure what they’re up to. $GLMD

Safety and Efficacy of Autologous Umbilical Cord Stem Cells Infusion for Preterm Infants. Guangdong Women and Children Hospital.
I’m confused about what is so wrong with preterm infants that they need ‘stem cells’. Oh, China.

The Effects of Microgravity on Human Sperm. Parabolic Flight. Institut Universitari Dexeus.
God bless these intrepid researchers.

Personal
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Half of all US adults have had a family member sent to prison. So, obviously, criminal “justice” is a disaster in the US and we have to make major rollbacks. But why not also acknowledge the professional failure of the law enforcement apparatus that includes the FBI, DOJ (DC and USA/AUSAs), etc.? Grand juries, juries and judges are to blame as well. The U.S. didn’t become a police state by accident–everyone is culpable. I’m not frustrated–I think that comes clear in these blog pages. I just feel terrible for all the guys here with truly undeserved long-term sentences. The accusers are often more guilty than the accused!

Government shutdown? Sounds great to me. Some of it should be permanently shut down!

Is Ruth Bader Ginsberg okay? Can someone check please?

Glossary
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I’m going to make this section iterative. We’ll start with simple definitions for some terms and “update” them over time.

dentate gyrus (updated): Part of the hippocampus, the DG receives input related to new stimuli from the entorhinal cortex. The DG is thought to be instrumental in forming new memories and spatial processing. The DG has granule cells with unique axonal projections called mossy fibers. Mossy cells constitute a substantial population of DG cells.

ribosome – The translation apparatus of the cell, using tRNA and mRNA to create proteins. Exceptionally complex, future definitions will build details.

syntenic – on the same chromosome, usually used when comparing conservation across organisms/orthologs

11 thoughts on “12/24/2018”

  1. Merry Christmas Martin,
    Hope you’re still having fun doing what you do – you’ve been really helpful in many ways to many people – thanks for that.
    Wishing you all the best,

    A thankful guy

  2. Merry Christmas, Shkrelz! I finally finished my J.D.!! Woot! Woot! I agree about the prosecutors, they are too focused on “winning” cases & getting a reputation, rather than doing what they are truly there to do. Cops are an enormous part of the problem & it’s incredulous what they get away with. I’m reading a book by Norm Champ, ‘Going Public-My Adventures at the SEC’. This is an eye opener, get it! Please don’t speak ill of Notorious RBG… OR ELSE!!🧡

  3. Began learning about trading and the economy after watching several of your videos on your past streams. Although your insights are amazing, I can safely say that I do not possess the intellectual capability of understanding a lot of the things you have mastered. Nonetheless, I look forward to continue learning about trading and actively await your release. Happy holidays Shkreli.

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