Martino, M. | bioRxiv Science

bioRxiv2026

A multistable slow-fast model of affective state switching under circadian drive

Rhythmic mood fluctuations are often associated with circadian timing, but it remains unclear how daily rhythms that normally organize physiological affective variation also shape transitions into longer pathological episodes in bipolar disorder. We introduce a phenomenological slow-fast model of affective dynamics inspired by HPA-axis homeostatic feedback. A fast affective coordinate evolves on a multistable landscape whose geometry is shaped by a slow homeostatic variable, producing four stable wells: depression-like, physiological low, physiological high, and mania-like. Circadian input acts not as a local forcing term but as a periodic tilt of the global affective landscape. With intact barriers, this tilt entrains physiological low-high cycling; when outer barriers are weakened, it creates phase-dependent windows for stochastic escape into pathological wells, where prolonged occupancy can produce episode-like infradian cycling. Modeling persistent perturbations as an Ornstein-Uhlenbeck process, we derive a Kramers-type escape criterion linking pathological transitions to phase-dependent barrier height and perturbation strength. One-year simulations and scans over the parameter governing landscape geometry show that preserved circadian amplitude stabilizes physiological cycling, whereas reduced amplitude combined with stronger perturbations promotes entry into and occupancy within depression-like or mania-like wells. The model provides a dynamical framework for studying how circadian disruption, landscape geometry, and perturbation sensitivity jointly shape transitions between physiological mood cycling and episode-like pathological states. Lead ParagraphBipolar disorder involves large, persistent transitions among depressive, euthymic, and manic states, whereas everyday mood also shows smaller fluctuations over the day. Whether these two forms of affective variation can be understood within a single dynamical framework remains unclear. Here, we present a slow-fast affective landscape model in which a slow homeostatic variable shapes a multistable potential for a faster affective state. The landscape contains two inner physiological wells and two outer pathological wells. Circadian input does not force the affective state directly into particular wells; instead, it periodically tilts the global landscape, entraining daily cycling within the physiological low and high states under normal geometry. When circadian amplitude is weakened or outer barriers are reduced, persistent stochastic fluctuations can promote escape into hard-to-exit depression-like or mania-like states. The central issue is therefore not simply whether such escapes can occur, but how circadian disruption, landscape geometry, and perturbation sensitivity determine the balance of dwell time across physiological and pathological states over clinically meaningful observation windows.

biophysics↗

bioRxiv2026

A distal CTCF-binding site drives MYC expression plasticity in a negative feed-forward loop

Oncogene expression heterogeneity systemically diversifies cancer cell phenotypes, enabling selection and cancer evolution. Here we document that the level of MYC expression variation is coordinated by a negative feed-forward loop involving the non-coding CCAT1 eRNA and the MYC gating process. While CCAT1 eRNA indirectly antagonizes MYC gating by promoting MYC transcriptional initiation and elongation, the MYC protein promotes gated MYC expression in a feedback loop by inhibiting both MYC transcription and CCAT1 expression. This entire process is coordinated by a CTCF binding site positioned within CCAT1 at a distal, oncogenic super-enhancer, which functions as a master switch by coordinating both CCAT1 and gated MYC expression to diversify cells toward both low and high MYC levels, as determined by heterogeneity metrics. As hallmarks of this principle are frequent in breast cancer and colorectal tumors, the dynamics of this new principle may underlie transitions between therapy-resistant low-MYC, and proliferative high-MYC tumor cells. Highlights- Transcriptional rate regulates MYC gating frequency - CCAT1 expression indirectly inhibits MYC gating by promoting MYC transcription - High MYC protein levels promote gated expression by inhibiting both MYC transcription and CCAT1 expression - These features are controlled by a single CTCF binding in the distant super-enhancer to drive expression plasticity in colorectal cancer cells

cancer biology↗

bioRxiv2019

NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress is associated with dysregulated metabolism, but little is known about how the ER responds to metabolic activity. Here, working primarily in mouse hepatocytes, we show that decreasing the availability of substrate for the TCA cycle diminished NADPH production and attenuated ER stress in a manner that depended on glutathione oxidation. ER stress was also alleviated by impairing either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity favored NADPH production, glutathione reduction, and ER stress. Validating these findings, we show that deletion of the mitochondrial pyruvate carrier, which is known to decrease TCA cycle activity and protect the liver from diet-induced injury, also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. These results provide independent genetic evidence that mitochondrial oxidative metabolism is linked to ER homeostasis. Our results demonstrate a novel pathway of communication between mitochondria and the ER, through relay of redox metabolites.

cell biology↗