Notes: Chapter 9: Metastability
Chapter notes for “Chapter 9: Metastability”
Notes
1 Peter Sterling and Joseph Eyer, “Allostasis: A New Paradigm to Explain Arousal Pathology,” in Handbook of Life Stress, Cognition and Health (1988). Sterling later developed the concept further in What Is Health? Allostasis and the Evolution of Human Design (2020).
1a For stem cell inflammatory memory in skin: Naik, S. et al., “Inflammatory memory sensitizes skin epithelial stem cells to tissue damage,” Nature 550 (2017): 475-480. Mice with prior skin inflammation healed subsequent wounds 2.5 times faster, with the memory persisting up to six months via epigenetic modifications (chromatin accessibility changes) in the stem cells. For the maladaptive version in human sinusitis: Ordovas-Montañes, J. et al., “Allergic inflammatory memory in human respiratory epithelial progenitor cells,” Nature 560 (2018): 649-654. Stem cells from chronic sinusitis patients retained active allergic inflammation gene signatures for over five weeks in culture, long after removal from the inflamed environment. See also Brouillette, M., “Stem Cells Remember Tissues’ Past Injuries,” Quanta Magazine (November 12, 2018).
1b Marco, A., Meharena, H.S., Dileep, V., et al., “Mapping the epigenomic and transcriptomic interplay during memory formation and recall in the hippocampal engram ensemble,” Nature Neuroscience 23 (2020): 1606–1617. doi: 10.1038/s41593-020-00717-0. Memory formation in mice restructures chromatin in hippocampal engram cells: enhancer regions become accessible and reposition closer to target genes, but full gene activation occurs only upon memory recall days later. The formation event primes; the recall event fires. Research conducted at MIT’s Picower Institute for Learning and Memory (Li-Huei Tsai laboratory).
2 Amruthesh Thirumalaiswamy et al., “Slow relaxation and landscape-driven dynamics in viscous ripening foams,” Proceedings of the National Academy of Sciences 122(47) (2025): e2518994122. doi: 10.1073/pnas.2518994122. The mathematical parallel to deep learning was identified by John C. Crocker’s lab at Penn Engineering. The same gradient descent mathematics that optimizes neural networks describes how bubbles move through configuration space — both systems exploring flat regions rather than locking into deep valleys.
3 Wahei Hagiwara and Lauren Sallan, “Mass extinction triggered the early radiations of jawed vertebrates and their jawless relatives (gnathostomes),” Science Advances 12:2 (2026): eaeb2297. The post-extinction “gap” of apparent low biodiversity was revealed through biogeographic reconstruction to be a period of hidden diversification in geographically isolated refugia, particularly South China. See Chapter 7 for the full account.
4 The phase diagram of water ice includes phases designated Ice I through Ice XIX, with several additional metastable and amorphous forms. For a comprehensive review: Christoph G. Salzmann, “Advances in the experimental exploration of water’s phase diagram,” Journal of Chemical Physics 150 (2019): 060901. Ice XVI, a negative-pressure clathrate form, was first synthesized in 2014; Ice XIX was confirmed in 2021.
6 Marius Millot et al., “Nanosecond X-ray diffraction of shock-compressed superionic water ice,” Nature 569 (2019): 251–255. The existence of superionic water was predicted theoretically in 1988 and first confirmed experimentally using diamond anvil cells and laser-driven shock compression. The distinct conductivity properties of these superionic phases and their implications for ice giant magnetic fields are discussed in Vitali B. Prakapenka et al., “Structure and properties of two superionic ice phases,” Nature Physics 17 (2021): 1233–1238.
6b He, Y., Sun, S., Kim, D.Y., et al., “Superionic iron alloys and their seismic velocities in Earth’s inner core,” Nature 602 (2022): 258–262. doi:10.1038/s41586-021-04361-x. Ab initio molecular dynamics simulations showing that hydrogen, oxygen, and carbon adopt liquid-like diffusive behavior within an hcp-Fe lattice at inner-core pressures and temperatures, resolving the long-standing discrepancy between seismically inferred shear properties and the expected behavior of pure crystalline iron. Experimental validation at partial inner-core conditions achieved by Zhang et al., “Experimental evidence for superionic Fe–C alloy revealed by shear softening in Earth’s inner core,” National Science Review 12(11) (2025): nwaf419. The authors of the 2022 paper explicitly discuss implications for geodynamo energetics: exchange of light elements between the inner and outer core alters buoyancy flux and may contribute to magnetic field stability.
5 The hierarchical supercoiling model (30nm fiber wound into solenoids, loops, and higher-order coils) was popularized by Drew Berry’s acclaimed 2003 molecular animation. The replacement came from polymer physics: Alexander Grosberg, Sergei Nechaev, and Eugene Shakhnovich predicted in 1988 that rapidly collapsed polymer chains would form crumpled globules—knot-free, self-similar, spatially segregated structures maintained out of equilibrium by topological constraints (chains can’t pass through each other). In 1993, Grosberg applied this to DNA, arguing that chromosomes must exist as crumpled globules because the equilibrium state (thoroughly knotted, randomly tangled) would be biologically useless. Twenty years later, Erez Lieberman-Aiden et al. confirmed the prediction using the Hi-C technique: “Comprehensive mapping of long-range interactions reveals folding principles of the human genome,” Science 326 (2009): 289-293. Contact probabilities, chromosome territories, and knot-free packing all matched the fractal globule model. No dedicated molecular machinery was required — physics did it for free, through a single topological constraint. See also: Grosberg, Nechaev, and Shakhnovich, “The role of topological constraints in the kinetics of collapse of macromolecules,” Journal de Physique 49 (1988): 2095-2100; Grosberg et al., “Crumpled Globule Model of the Three-Dimensional Structure of DNA,” Europhysics Letters 23 (1993): 373-378; Mirny, “The fractal globule as a model of chromatin architecture in the cell,” Chromosome Research 19 (2011): 37-51. Robin Bruinsma’s discussion of this transition appears in his Aspen Center for Physics lecture, “The Physics of DNA.”
7a Brangwynne, C.P., Eckmann, C.R., Courson, D.S. et al., “Germline P granules are liquid droplets that localize by controlled dissolution/condensation,” Science 324 (2009): 1729-1732. The discovery that P granules in C. elegans are liquid droplets, not solid pellets. For the cytoplasmic solidification survival mechanism: Alberti, S. et al., “A physicochemical framework for intracellular phase transitions,” Molecular Cell 79:2 (2020): 251-264; and Munder, M.C., et al., “A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy,” eLife 5 (2016): e09347. For protein domain tuning of reversibility: Kato, M. et al., “Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels,” Cell 149:4 (2012): 753-767. For the connection to neurodegenerative disease: Patel, A. et al., “A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation,” Cell 162:5 (2015): 1066-1077. See also Moskvitch, K., “‘Lava-Lamp’ Proteins May Help Cells Cheat Death,” Quanta Magazine (November 26, 2018).
7 Bas van de Schootbrugge et al., “Recognition of an extended record of euglenoid cysts: Implications for the end-Triassic mass extinction,” Review of Palaeobotany and Palynology 322 (2024): 105043. The study reviewed approximately 500 literature sources to connect four form genera—Chomotriletes (Paleozoic), Circulisporites (Permian), Pseudoschizaea (Mesozoic, described since 1962), and Concentricystes (Quaternary)—as euglenoid cysts from different geological periods. Transmission electron microscopy of cyst wall ultrastructure confirmed the identification. Co-author Fabian Weston, a microscopist in Sydney, filmed the first known video of euglena encystment when a drop of pond water from New South Wales evaporated on a slide — Paul Strother of Boston College called him “probably the only person on the planet” to have witnessed the process under a microscope.
7d Tang, H.L. et al. “Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response.” Molecular Biology of the Cell 23, 2240–2252 (2012). The term “anastasis” was introduced in this paper.
7e Sun, G. et al. “A molecular signature for anastasis, recovery from the brink of apoptotic cell death.” Journal of Cell Biology 216(10), 3355–3368 (2017). This study, from Montell’s lab at UCSB, identified the two-phase recovery program and showed that growth-promoting genes are expressed concurrently with apoptotic markers.
7f Lennon, J.T. and Jones, S.E. “Microbial seed banks: the ecological and evolutionary implications of dormancy.” Nature Reviews Microbiology 9 (2011): 119–130, establishing that the majority of microbial cells in most environments are metabolically inactive at any given time. The more specific estimate that at least 60 percent of global microbial biomass exists in some form of dormancy is a synthesis figure common across the subsequent dormancy literature rather than a single measured value; the precise fraction is measurement-dependent, since active-versus-inactive determinations vary by method. [Unverified]
7g Helena-Bueno, K., Rybak, M., and Melnikov, S. “A ubiquitous protein drives ribosome hibernation via rapid and reversible stalling of translation.” Nature (2024). Balon binds near but not across the ribosomal A site, allowing insertion and ejection regardless of the ribosome’s current activity, a mechanism without precedent among known hibernation factors.
9 William W. Crockett, Jack O. Shaw, Carl Simpson, and Christopher P. Kempes, “Physical constraints during Snowball Earth drive the evolution of multicellularity,” Proceedings of the Royal Society B 291 (2024): 20232767. The theoretical framework; for the experimental confirmation with green algae evolving motile multicellular phenotypes under Snowball Earth viscosities, see Peter J. Halling et al., bioRxiv (2024). Phenotypes persisted for over a hundred generations after return to normal conditions. See Chapter 7 for the full account of the viscosity hypothesis and its relationship to the Avalon explosion.
9d Tarnita, C.E. et al., “A theoretical foundation for multi-scale regular vegetation patterns,” Nature 541 (2017): 398–401. The study combined imaging, mathematical modeling, and field data from Namibia to show that termite-driven and vegetation self-organization patterns operate at distinct spatial scales and together explain the fairy circle landscape.
8 The 2016 Yamal Peninsula anthrax outbreak: B. Revich and M. Podolnaya, “Thawing of permafrost may disturb historic cattle burial grounds in East Siberia,” Global Health Action 4 (2011): 8482, warned of the risk years before the event. For the outbreak itself: Stella Hurtado, “Anthrax outbreak in Siberia,” The Lancet Infectious Diseases 16:9 (2016): 1008. Approximately 2,300 reindeer died and 36 humans were hospitalized; a 12-year-old boy died. The source was traced to thawed permafrost exposing animal carcasses containing viable Bacillus anthracis spores. For ancient virus revival: Jean-Michel Claverie et al., “An ancient virus revived from 30,000-year-old permafrost,” PNAS 111:11 (2014): 4274–4279, and subsequent work by the same group reviving Pithovirus, Mollivirus, and Pandoravirus from Siberian permafrost samples up to approximately 48,500 years old: Jean-Marie Alempic et al., “An update on eukaryotic viruses revived from ancient permafrost,” Viruses 15:2 (2023): 564.
10 The core microbiome’s age-related decline: Edoardo Pasolli et al., “Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle,” Cell 176:3 (2019): 649–662, characterizes shifts in microbial composition across age cohorts. For the longevity-microbiome link: Elena Biagi et al., “Gut Microbiota and Extreme Longevity,” Current Biology 26:11 (2016): 1480–1485, identified the core consortium’s decline and subdominant species expansion in centenarians. The inflammaging framework: Claudio Franceschi et al., “Inflammaging: a new immune-metabolic viewpoint for age-related diseases,” Nature Reviews Endocrinology 14 (2018): 576–590. For Valenzano’s microbiome-aging work in the turquoise killifish: Patrick Smith et al., “Regulation of life span by the gut microbiota in the short-lived African turquoise killifish,” eLife 6 (2017): e27014; and his theoretical framework: Mélanie Popkes and Dario Riccardo Valenzano, “Microbiota–host interactions shape ageing dynamics,” Philosophical Transactions of the Royal Society B 375 (2020): 20190596.
11 Germ-free mouse longevity: S. Tazume et al., “Effects of germfree status and food restriction on longevity and growth of mice,” Experimental Animals 40 (1991): 517–522. See also H. A. Gordon et al., “Aging in germ-free mice: life tables and lesions observed at natural death,” Journal of Gerontology 21 (1966): 380–387.
12 Clea Barcena et al., “Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice,” Nature Medicine 25 (2019): 1234–1242. Progeroid models used were Zmpste24-/- and LmnaG609G/G609G mice (nuclear envelope mutations causing accelerated aging). Wild-type FMT reversed gut dysbiosis, restored secondary bile acid metabolism, and significantly extended lifespan. In particular, Akkermansia muciniphila alone was sufficient for much of the benefit.
13 The historical decline in human body temperature: Myroslava Protsiv et al., “Decreasing human body temperature in the United States since the Industrial Revolution,” eLife 9 (2020): e49555, analyzed 677,423 temperature measurements spanning 157 years and confirmed a decline of approximately 0.03°C per birth decade since the 1860s. The microbiome-temperature link: Robert P. Dickson et al. have characterized associations between gut bacterial composition and thermoregulatory response during critical illness; see also work on germ-free mouse thermoregulation showing reduced basal body temperature in the absence of gut microbiota. For the metabolic disorder connection: Peter J. Turnbaugh et al., “An obesity-associated gut microbiome with increased capacity for energy harvest,” Nature 444 (2006): 1027–1031, demonstrated that obese mice harbor a microbiome that extracts more calories from the same diet — the consortium’s metabolic contribution varies with composition, directly influencing energy balance and weight regulation.
14 Microclots in long COVID were first characterized by Etheresia Pretorius et al., “Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin,” Cardiovascular Diabetology 20 (2021): 172. The twenty-fold elevation and amyloid-like fibrin structure: Pretorius et al., “Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19,” Cardiovascular Diabetology 21 (2022): 148. For the structural association between NETs and microclots, and the machine learning classifier achieving 91 percent diagnostic accuracy: Alain R. Thierry, Tom Usher, Cynthia Sanchez, Simone Turner, Chantelle Venter, et al., “Circulating Microclots Are Structurally Associated With Neutrophil Extracellular Traps and Their Amounts Are Elevated in Long COVID Patients,” Journal of Medical Virology 97:10 (2025): e70613. doi:10.1002/jmv.70613. The spike protein’s role in triggering amyloid fibrin formation: Grobbelaar et al., “SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19,” Bioscience Reports 41:8 (2021): BSR20210611.
15 Ehrenfest, Paul, “In what way does it become manifest in the fundamental laws of physics that space has three dimensions?” Proceedings of the Amsterdam Academy 20 (1917): 200–209. Ehrenfest showed that stable planetary orbits and stable atomic structures are possible only in exactly three spatial dimensions — in four or more dimensions, inverse-square force laws cannot produce closed stable orbits. [Note: An earlier version of this passage attributed the result to Bertrand’s theorem (1873), which concerns a different question — which central force laws produce closed orbits in three dimensions. The dimensional instability argument is Ehrenfest’s.]
16 Du, K., et al., “Hybridization reveals divergence in reproductive compatibility between gar species,” Proceedings of the Royal Society B 289 (2022): 20221267. See also Brownstein, C.D., et al., “The genomic signatures of evolutionary stasis,” Evolution 78:5 (2024): 821–834, for the molecular evidence that gars possess the slowest rate of molecular evolution recorded among jawed vertebrates, attributable to exceptionally efficient DNA repair machinery.
16c Cao, Y. et al., “Unconventional superconductivity in magic-angle graphene superlattices,” Nature 556 (2018): 43–50; Cao, Y. et al., “Correlated insulator behavior at half-filling in magic-angle graphene superlattices,” Nature 556 (2018): 80–84. At exactly 1.1 degrees of twist, the electrons’ effective velocity vanishes and the lowest energy bands flatten (as predicted by Bistritzer, R. and MacDonald, A.H., “Moiré bands in twisted double-layer graphene,” PNAS 108 (2011): 12233–12237), electrons become strongly correlated, and the material can be switched between conductor, insulator, and superconductor by varying an external electric field. The magic angle is remarkably precise (graphene sheets actively resist holding it) and the superconducting transition temperature (~1.7 K, later pushed to ~3 K by Efetov’s group) occurs at unprecedentedly low electron densities.
16b Degrassi, G., Di Vita, S., Elias-Miró, J., Espinosa, J.R., Giudice, G.F., Isidori, G., and Strumia, A., “Higgs mass and vacuum stability in the Standard Model at NNLO,” Journal of High Energy Physics 2012, 98 (2012). doi:10.1007/JHEP08(2012)098. Using the measured Higgs boson mass (~125.1 GeV) and top quark mass (~173 GeV), the authors calculated that the electroweak vacuum lies in a metastable region of the Standard Model phase diagram — a local minimum separated from the true vacuum by a barrier so large that the tunneling probability is negligible over the lifetime of the universe. See also Buttazzo, D., et al., “Investigating the near-criticality of the Higgs boson,” Journal of High Energy Physics 2013, 89 (2013), which refined the analysis and noted the striking proximity of the measured parameters to the boundary between stability and metastability.
17 Wibowo, M.C., et al., “Reconstruction of ancient microbial genomes from the human gut,” Nature 594 (2021): 234–239. Metagenomic analysis of paleofeces (coprolites) from archaeological sites up to 2,000 years old, recovering near-complete bacterial genomes and demonstrating that pre-industrial gut microbiomes harbored greater species diversity and more transposase genes than modern industrialized populations.
18 Global Burden of Disease Long COVID Collaborators, “Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021,” JAMA 328 (2022): 1604–1615. Systematic analysis estimating that 6.2% of symptomatic COVID-19 infections produced at least one long COVID symptom cluster persisting beyond three months.
19 Xu, C., Xu, J., Tang, H.-W., Ericsson, M., Weng, J.-H., DiRusso, J., Hu, Y., Ma, W., Asara, J.M., and Perrimon, N., “A phosphate-sensing organelle regulates phosphate and tissue homeostasis,” Nature 617(7962) (2023): 798–806. doi: 10.1038/s41586-023-06039-y. PXo bodies are non-canonical multilamellar organelles discovered in Drosophila midgut epithelium that serve as intracellular phosphate reservoirs — capturing excess phosphate and releasing it when levels drop. Research conducted at Harvard Medical School (Norbert Perrimon lab).
20 Goldberger, A.L., et al., “Fractal dynamics in physiology: alterations with disease and aging,” PNAS 99 (2002): 2466–2472. Goldberger’s group demonstrated that healthy physiological systems exhibit fractal scaling (long-range correlations across multiple timescales) and that the breakdown of this fractal complexity (toward either excessive regularity or excessive randomness) is a hallmark of disease and aging.
21 Hausdorff, J.M., et al., “Altered fractal dynamics of gait: reduced stride-interval correlations with aging and Huntington’s disease,” Journal of Applied Physiology 82 (1997): 262–269. Demonstrated that healthy gait exhibits long-range fractal correlations in stride timing, and that these correlations break down with aging and neurodegenerative disease — paralleling the loss of fractal complexity in cardiac dynamics.
21a Al, Esra, Iliopoulos, Fivos, Forschack, Norman, et al., “Heart–brain interactions shape somatosensory perception and evoked potentials,” Proceedings of the National Academy of Sciences 117(19) (2020): 10575–10584. Participants were more likely to perceive a barely detectable electrical stimulus during cardiac diastole than during systole, demonstrating that the heartbeat gates conscious access to external stimuli.
21b Garfinkel, Sarah N., Minati, Ludovico, Gray, Marcus A., Seth, Anil K., Dolan, Raymond J., and Critchley, Hugo D., “Fear from the heart: sensitivity to fear stimuli depends on individual heartbeats,” Journal of Neuroscience 34(19) (2014): 6573–6582. Fear processing is enhanced during cardiac systole (the phase that suppresses other external signals) through selective amygdala activation.
21c Bradley, James A., Amend, Jan P., and LaRowe, Douglas E., “Survival of the fewest: Microbial dormancy and maintenance in marine sediments through deep time,” Science Advances 6(32) (2020): eabc0697. Global model of sub-seafloor biosphere showing microbes surviving at power levels approaching the theoretical minimum for life (~10-21 watts per cell). See also LaRowe, D.E. and Amend, J.P., “Power limits for microbial life,” Frontiers in Microbiology 6 (2015): 718, for the theoretical zeptowatt minimum.
9b Bak, Per, Chao Tang, and Kurt Wiesenfeld, “Self-organized criticality: An explanation of the 1/f noise,” Physical Review Letters 59(4) (1987): 381–384. Bak and colleagues demonstrated that many complex systems (sandpiles, earthquakes, neural networks) self-organize to critical states without external tuning, producing scale-invariant (power-law) behavior. The critical state is an attractor: the dynamics drive the system toward it regardless of initial conditions. See also Bak, Per, How Nature Works: The Science of Self-Organized Criticality (Copernicus, 1996). The connection to metastability: the flat plateaus and broad basins described in this chapter are the configurational signature of self-organized criticality — the system finds the edge because the edge is where the dynamics lead.
9c Michel Fruchart, Ryo Hanai, Peter B. Littlewood, and Vincenzo Vitelli, “Non-reciprocal phase transitions,” Nature 592 (2021): 363-369. The team demonstrated that exceptional points (singularities where two or more characteristic properties of a system become indistinguishable) govern phase transitions in nonreciprocal, out-of-equilibrium systems. The robot demonstrations and polariton condensate analysis showed that the language of energy minimization, which describes equilibrium phase transitions, fails for systems where energy is continuously added and dissipated. Bifurcation theory replaces the energy landscape as the appropriate mathematical framework. A complementary result extends these systems’ analytic reach: Yu-Bo Shi, Roderich Moessner, Ricard Alert, and Marin Bukov, “Hamiltonian description of non-reciprocal interactions,” Nature Physics (2026), DOI: 10.1038/s41567-026-03317-0, embed non-reciprocal dynamics in a constrained Hamiltonian by pairing each degree of freedom with a fictitious “mirror” partner, restoring Monte-Carlo and Floquet tools for simulation. The embedding Hamiltonian vanishes on the constraint surface where the real dynamics live, so it generates those dynamics without serving as an energy; the system stays out of equilibrium, and energy-minimization language is not recovered.
9e Stringer, Carsen, Marius Pachitariu, Nicholas Steinmetz, Matteo Carandini, and Kenneth D. Harris, “High-dimensional geometry of population responses in visual cortex,” Nature 571 (2019): 361–365. Roughly 10,000 neurons were recorded simultaneously in mouse visual cortex during presentation of about 2,800 natural images. Neural representations follow a power law whose exponent sits at the boundary between maximum dimensionality and smoothness: slower decay would make representations fractal, so that small input changes produce large output changes, while faster decay would sacrifice information.
9f Jang, Hyunwoo, George A. Mashour, Anthony G. Hudetz, and Zirui Huang, “Measuring the dynamic balance of integration and segregation underlying consciousness, anesthesia, and sleep in humans,” Nature Communications 15, 9164 (2024). doi:10.1038/s41467-024-53299-x. The integration-segregation difference (ISD) is defined as multi-level network efficiency minus clustering coefficient. Across six independent fMRI datasets, ISD sits near zero in awake brains and shifts negative under propofol anesthesia and N2 sleep. The hysteresis in ISD trajectories between loss and recovery of consciousness is the paper’s support for the neural inertia hypothesis.
22 Scheffer, M., et al., “Catastrophic shifts in ecosystems,” Nature 413 (2001): 591–596. Scheffer’s influential review formalized the concept of critical transitions in ecosystems, showing that lakes, coral reefs, forests, and other systems can undergo sudden, difficult-to-reverse shifts between alternative stable states when perturbation exceeds a threshold.
23 Kim, Jaekyung, Tanuj Gulati, and Karunesh Ganguly, “Competing roles of slow oscillations and delta waves in memory consolidation versus forgetting,” Cell 179 (2019): 514–526. Slow oscillations were distinguished from delta waves during non-REM sleep in rats learning a motor skill: disrupting slow oscillations impaired memory, while disrupting delta waves improved it. The two wave types compete to synchronize with sleep spindles, and which one wins determines whether a memory is strengthened or weakened.