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Week 1 in the Books!

 

Greetings from snowy Park City!

 

I started Abstract Watch on Tuesday, Nov 1, 2022. Hoping to build a healthy new habit, learn new science, challenge myself, and find joy in new discoveries. I'd say it's off to a great start. This initiative has reminded me of how good it feels to 'practice' something - we often associate practice with meditation, or yoga, or a hobby, or a profession - but showing up and reading a new abstract every day is a practice. It has cumulative effects that grow your skill and expand your comfort zone. 

 

I'm listing the Abstracts we covered this week below. In all honesty I ended up reading beyond the abstract to fully understand the advance. Maybe that will improve in time... maybe it's me, maybe it's the abstract ;) I'm posting links to the preprints below if there is one, because I was extremely grateful the full paper was open access somewhere. That being said, I am also grateful to the journals for the curation, many of these papers I would have never found if they weren't published in journals that I look at. I know that is not the case for everyone, and that many of you do more directed searches, but for me, perusing the vast literature of science, I rely on reputable journals. 

 

Abstract Watch #1 "Programmable RNA sensing for cell monitoring and manipulation" from Josh Huang's lab at Duke. This new method that uses the presence of a cell-specific RNA to drive translation of a reporter or other payload.Twitter pointed me to the related paper "Programmable eukaryotic protein synthesis with RNA sensors by harnessing ADAR". Both methods introduce a transcript with a 5'sensor and 3'effector, separated by a UAG stop codon. When the 5'sensor base pairs with a target mRNA, the A-to-I editing enzyme ADAR (expressed in all cells) converts the UAG to UIG (Trp) leading to translation of the 3' effector. Fig1 from Jiang et al was super helpful.

This method is a FAST and DIRECT approach to detect/manipulate cells that have your mRNA of interest - whether or not the promoter is on.

 

Abstract Watch #2 "X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women" From the Kang-Woo lab at Case Western Reserve University. Beautifully written, compelling & clear abstract, highlights, graphic abstract. X-linked USP11 deubiquitinates tau, which enhances acetylation & aggregation USP11 escapes dosage compensation so is higher in females.USP11 levels correlate strongly with tau brain pathology in females but not males. Elimination of usp11 in mice reduces tau pathology and cognitive impairment in females more than males. Very cool example of gene dosage imbalance in XX vs XY potentially underlying sex specific disease susceptibility. And hopeful because the enzymatic activity of USP11 could potentially be inhibited.

Abstract watch #3 "Quorum-sensing- and type VI secretion-mediated spatiotemporal cell death drives genetic diversity in Vibrio cholerae" from the Bassler lab at Princeton. Some basics: Bacteria track cell population density by quorum sensing (QS), which involves producing & detecting of extracellular signals. The V. cholerae type VI secretion system (T6SS) is a QS-regulated, contact-dependent system that enables attack & elimination of cells. The paper shows that colonies initially composed of genetically identical cells undergo 2 phases of T6SS-mediated cell death, driven by distinct T6SS effectors. Fig S7J was *essential* for me to get the concept.

The 1st phase of cell death, at the rim, is regulated by regional differences in QS and t6ss gene expression. T6SS-driven killing imposes a selective pressure. QS lof mutants that are protected from T6SS-mediated killing arise as sectors. The 2nd phase, in the interior, also requires a T6SS toxin but does not affect sectoring and does not rely on the T6SS-injection apparatus. Phase 1 cell death is key for sectoring to occur and, therefore, for enhanced genetic diversity to arise in the population. Cool discussion point: Cells residing in colonies compete for limited resources, including space and nutrients, and they found that growth in resource-rich nutrient broth suppressed cell death and sectoring. So, the take home? Resource limitation promotes death via quorum sensing, and the emergence of new traits & variants within a homogeneous colony. This has implications for all sorts of biology - cell competition in other organisms & other contexts.

 

Abstract Watch #4 "Pseudouridine-dependent ribosome biogenesis regulates translation of polyglutamine proteins during Drosophila oogenesis" from Elizabeth Gavis at Princeton & Prashanth Rangan at the Icahn School of Medicine. The paper shows that the rRNA pseudouridine synthase "H/ACA box" is required for oocyte specification in Drosophila. Loss of the H/ACA box reduced riobosome biogenesis during oogenesis, and in particular reduced translation of a *subset* of mRNAs. Intriguingly (!) these mRNAs were enriched for CAGs in their coding sequence, and encode proteins with polyglutamine (polyQ) stretches, including polyQ proteins that are required to specify an oocyte. They also showed that modulating ribosome levels by manipulating the Target of Rapamycin (TOR) pathway affected translation of polyQ proteins and oocyte specification. The work shows the translation of mRNAs that encode polyQ proteins is sensitive to ribosome levels, and that many proteins required for oocyte specification are polyQ proteins. Therefore, this process is regulated by ribosome levels. The work also suggests that TOR inhibitors, generated to primarily treat cancers, could potentially be repurposed to reduce polyQ protein aggregation in various disease states.

 

Abstract Watch #5 "Group II intron-like reverse transcriptases function in double-strand break repair" from Alan Lambowitz at U Texas Austin. Bkgd: group II introns are in bacteria & are retrotransposons that are evolutionary ancestors of spliceosomal introns, the spliceosome, & other retroelements in eukaryotes. They encode a reverse transcriptase (RT). RTs generate complementary DNA from an *RNA template*, & are used by retroviruses, by retrotransposons, & by telomerase. The authors found that loss (KO) of the group II-like 4 (G2L4) RT in Pseudomonas aeruginosa led to upregulation of DNA repair genes & the KO was more sensitive to DNA damage. They demonstrated that G2L4 & a G2 intron RT could use DNA as a template & read through DNA lesions. They showed that G2L4 RT & GII RT can function in microhomology-mediated end-joining in vitro & in vivo. Cool discussion points: Close structural similarity between G2 and non-LTR-retroelement RTs & the finding that MMEJ by these RTs is dependent upon the RT0 loop, a conserved feature of non-LTR-retroelement RTs, suggests that nonLTR-retroelement RTs may function in DSBR (!) "non-LTR-retrotransposon RTs may function not only in producing cDNAs that are integrated at DSBs, but may also play an active role in repairing DSBs by mechanisms similar to those elucidated here for G2L4 and GII RTs." and "human LINE-1 and other non-LTR retroelement RTs may not only mitigate damage caused by their retrotransposition, but also **provide a benefit to their host organisms in exchange for proliferating within their genomes.**".

 

 

Abstract Watch #6 "In vivo direct imaging of neuronal activity at high temporospatial resolution" from Jeehyun Kwang (Korea University) and Jang-Yeon Park (Sungkyunkwan University) labs in South Korea. The preprint (again) helped me identify the knowledge gap: Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level dependent (BOLD) effect has good spatial resolution (millimeters), but poor temporal resolution (seconds) due to slow hemodynamic responses. Electro- and magneto-encephalography have good temporal resolution (millisecond), but poor spatial resolution (centimeter). **Increased MRI-based temporal resolution is needed to advance the understanding of causal link between in vivo neuronal activities & brain function.** The paper reports DIANA (direct imaging of neuronal activity), a two-dimensional fast line-scan approach that allows direct mapping of neuronal activity in a living mouse’s brain with high temporal (5 millisecond) and spatial (0.22 millimeter) resolution. “The ability of DIANA to lift the temporal and spatial hurdles that now limit BOLD-fMRI holds the exciting potential to reveal the detailed computational mechanisms of mental processing at the fast pace at which it unfolds” Kerkoerle and Cloos. Predictions based on neuronal density, magnetic field strength, & typical voxel size in mouse vs human systems suggest that DIANA-fMRI is likely to work in human studies, but more complicated responses are expected to be observed in human brain networks. As an aside - Uri Hasson does great work using fMRI & other approaches to understand how we communicate - and has a great TED talk on it.

 

Whew! I am clearly "out of shape"! Hopefully my efficiency and brevity will improve over time.

 

See you tomorrow, at the start of Week 2!

 

Ang