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“If their DNA could be retrained, maybe microbes could deliver nitrogen directly to wheat, corn, and other crops when it’s most needed.” Chris Voigt is helping turn that idea into reality by engineering microbes to work harder and smarter. Read his story:

20,336 Aufrufe • vor 7 Tagen •via X (Twitter)

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Some microbes carry a protein, called SNIPE, that "chops up" phage DNA as it's being injected into the cell. This is a new mechanism for phage defense! CRISPR–Cas and restriction enzymes also evolved to fight against phages, but they work by recognizing sequences. SNIPE works, instead, by sensing "touch." SNIPE is a protein with about 500 amino acids. After it's made by the ribosome, it latches onto ManYZ, two proteins which sit on the cell's inner membrane. (ManYZ is an importer; it brings mannose and other sugars into the cell.) Once attached to ManYZ, SNIPE sits and waits for an invading phage. Some phages, including lambda, actually infect cells by pushing their DNA through this ManYZ channel. Lambda uses its "tail" to reach inside the protein channel, basically, and inject its DNA. When this physical touch happens, though, SNIPE is waiting. As soon as the phage DNA starts entering the cell, and passes through ManYZ and SNIPE, it gets immediately destroyed. This means that SNIPE is the first phage defense system discovered, so far, that uses spatial positioning at the injection site to destroy invaders. But there are caveats, of course. If you untether SNIPE from ManYZ, such that it can freely diffuse through the cell, it will chew up the bacterium's genome. It is not a highly discerning nuclease! Also, SNIPE is not found in most bacteria. A prior pangenome study, which sequenced lots of different microbes, found that roughly a third of well-studied bacterial lineages had at least one member with a SNIPE-like protein. (For this paper, they just ported one of those homologs into an E. coli laboratory strain.) And finally, because SNIPE's mechanism is tightly tied to ManYZ, it cannot be used to defend against phages that enter the cell through different routes. T4 phages, for example, inject their DNA straight through the cell membrane and into the cytoplasm, without interacting with ManYZ. This is a nice basic science paper. Applications TBD. (Just remember that scientists figured out that bacteria had a phage defense system, called CRISPR-Cas, many years before it was repurposed into a gene-editing tool.) P.S. The video below shows how cells with the SNIPE gene (middle row) kill invading phages, and thus continue growing and dividing. Empty vector (top row) refers to bacteria carrying a plasmid with no SNIPE gene; this is a control group. And SNIPE E414A refers to cells which received a mutated SNIPE gene, where the glutamate at position 414 has been changed to an alanine, thus destroying the protein's nuclease activity. These cells also die when they get infected with a phage.

Niko McCarty.

20,536 Aufrufe • vor 5 Monaten

Today was my hardest workout before the Javelina 100—an uphill treadmill supercompensation session accumulating 60 minutes of intervals at 10% grade, starting at threshold and ending harder. I think uphill treadmill threshold sessions can be magical for some athletes. Threshold work is classically defined as LT2 or easier, around what you could sustain for 1 hour. In practice, that feels relatively relaxed at first, and it only starts to get harder after you accumulate a substantial amount of volume. The rationale of threshold work is that it improves lactate shuttling, helping mitochondria be more efficient at processing and transporting lactate, preventing fatigue cascades even at harder efforts on other days (or at easier efforts in marathons or ultras). In other words, it’s primarily an aerobic stress. Faster is not better. The real-world obstacles with threshold work are twofold. First, for most of us, it’s pretty slow when done right, or way too hard when done wrong. A study on the training of elite athletes found that long intervals had the lowest correlation with long-term growth, and this conundrum is probably why—athletes do their long intervals too hard, breaking themselves down without the mechanical or aerobic stimulus to justify it. Second, outdoor threshold work can be an injury risk. If I tried this workout outdoors, it would wreck my calves and high hamstrings for days. The uphill treadmill can help athletes get around these hurdles. It’s slower by design, putting the emphasis squarely on the aerobic system. That helps athletes develop a much more precise understanding of threshold. But perhaps most significantly, the uphill treadmill reduces impact forces immensely. When I finish one of these—even a supercompensation session—I feel fine the next day, allowing me to absorb way more work (and more specific work to my goals). Particularly with age, I find that running training is about managing the efforts that are high impact to be limited and focused. While most of the uphill treadmill work I do is very controlled, it’s also ok to occasionally dig deeper. Today was about supercompensation. It’s not called The Pain Cave for nothing 🔥

David Roche

40,681 Aufrufe • vor 1 Jahr