- Proceedings of the National Academy of Sciences of the United States of America
- Published 7 months ago
Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass.
Plants continuously extend their root and shoot systems through the action of meristems at their growing tips. By regulating which meristems are active, plants adjust their body plans to suit local environmental conditions. The transport network of the phytohormone auxin has been proposed to mediate this systemic growth coordination, due to its self-organising, environmentally sensitive properties. In particular, a positive feedback mechanism termed auxin transport canalization, which establishes auxin flow from active shoot meristems (auxin sources) to the roots (auxin sinks), has been proposed to mediate competition between shoot meristems and to balance shoot and root growth. Here we provide strong support for this hypothesis by demonstrating that a second hormone, strigolactone, regulates growth redistribution in the shoot by rapidly modulating auxin transport. A computational model in which strigolactone action is represented as an increase in the rate of removal of the auxin export protein, PIN1, from the plasma membrane can reproduce both the auxin transport and shoot branching phenotypes observed in various mutant combinations and strigolactone treatments, including the counterintuitive ability of strigolactones either to promote or inhibit shoot branching, depending on the auxin transport status of the plant. Consistent with this predicted mode of action, strigolactone signalling was found to trigger PIN1 depletion from the plasma membrane of xylem parenchyma cells in the stem. This effect could be detected within 10 minutes of strigolactone treatment and was independent of protein synthesis but dependent on clathrin-mediated membrane trafficking. Together these results support the hypothesis that growth across the plant shoot system is balanced by competition between shoot apices for a common auxin transport path to the root and that strigolactones regulate shoot branching by modulating this competition.
Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.
Circadian (∼24 h) timekeeping is essential for the lives of many organisms. To understand the biochemical mechanisms of this timekeeping, we have developed a detailed mathematical model of the mammalian circadian clock. Our model can accurately predict diverse experimental data including the phenotypes of mutations or knockdown of clock genes as well as the time courses and relative expression of clock transcripts and proteins. Using this model, we show how a universal motif of circadian timekeeping, where repressors tightly bind activators rather than directly binding to DNA, can generate oscillations when activators and repressors are in stoichiometric balance. Furthermore, we find that an additional slow negative feedback loop preserves this stoichiometric balance and maintains timekeeping with a fixed period. The role of this mechanism in generating robust rhythms is validated by analysis of a simple and general model and a previous model of the Drosophila circadian clock. We propose a double-negative feedback loop design for biological clocks whose period needs to be tightly regulated even with large changes in gene dosage.
Reverse engineering gene networks and identifying regulatory interactions are integral to understanding cellular decision making processes. Advancement in high throughput experimental techniques has initiated innovative data driven analysis of gene regulatory networks. However, inherent noise associated with biological systems requires numerous experimental replicates for reliable conclusions. Furthermore, evidence of robust algorithms directly exploiting basic biological traits are few. Such algorithms are expected to be efficient in their performance and robust in their prediction.
We identify robust statistical patterns in the frequency and severity of violent attacks by terrorist organizations as they grow and age. Using group-level static and dynamic analyses of terrorist events worldwide from 1968-2008 and a simulation model of organizational dynamics, we show that the production of violent events tends to accelerate with increasing size and experience. This coupling of frequency, experience and size arises from a fundamental positive feedback loop in which attacks lead to growth which leads to increased production of new attacks. In contrast, event severity is independent of both size and experience. Thus larger, more experienced organizations are more deadly because they attack more frequently, not because their attacks are more deadly, and large events are equally likely to come from large and small organizations. These results hold across political ideologies and time, suggesting that the frequency and severity of terrorism may be constrained by fundamental processes.
In a simulation experiment we studied the effects of cognitive, emotional, sensorimotor, and mixed stressors on driver arousal and performance with respect to (wrt) baseline. In a sample of n = 59 drivers, balanced in terms of age and gender, we found that all stressors incurred significant increases in mean sympathetic arousal accompanied by significant increases in mean absolute steering. The latter, translated to significantly larger range of lane departures only in the case of sensorimotor and mixed stressors, indicating more dangerous driving wrt baseline. In the case of cognitive or emotional stressors, often a smaller range of lane departures was observed, indicating safer driving wrt baseline. This paradox suggests an effective coping mechanism at work, which compensates erroneous reactions precipitated by cognitive or emotional conflict. This mechanisms' grip slips, however, when the feedback loop is intermittently severed by sensorimotor distractions. Interestingly, mixed stressors did not affect crash rates in startling events, suggesting that the coping mechanism’s compensation time scale is above the range of neurophysiological latency.
Self-propelled bacteria can be integrated into synthetic micromachines and act as biological propellers. So far, proposed designs suffer from low reproducibility, large noise levels or lack of tunability. Here we demonstrate that fast, reliable and tunable bio-hybrid micromotors can be obtained by the self-assembly of synthetic structures with genetically engineered biological propellers. The synthetic components consist of 3D interconnected structures having a rotating unit that can capture individual bacteria into an array of microchambers so that cells contribute maximally to the applied torque. Bacterial cells are smooth swimmers expressing a light-driven proton pump that allows to optically control their swimming speed. Using a spatial light modulator, we can address individual motors with tunable light intensities allowing the dynamic control of their rotational speeds. Applying a real-time feedback control loop, we can also command a set of micromotors to rotate in unison with a prescribed angular speed.
Our actions often do not match our intentions when there are external disturbances such as turbulence. We derived a novel modeling approach for determining this motor intent from targeted reaching motions that are disturbed by an unexpected force. First, we demonstrated how to mathematically invert both feedforward (predictive) and feedback controls to obtain an intended trajectory. We next examined the model’s sensitivity to a realistic range of parameter uncertainties, and found that the expected inaccuracy due to all possible parameter mis-estimations was less than typical movement-to-movement variations seen when humans reach to similar targets. The largest sensitivity arose mainly from uncertainty in joint stiffnesses. Humans cannot change their intent until they acquire sensory feedback, therefore we tested the hypothesis that a straight-line intent should be evident for at least the first 120 milliseconds following the onset of a disturbance. As expected, the intended trajectory showed no change from undisturbed reaching for more than 150 milliseconds after the disturbance onset. Beyond this point, however, we detected a change in intent in five out of eight subjects, surprisingly even when the hand is already near the target. Knowing such an intent signal is broadly applicable: enhanced human-machine interaction, the study of impaired intent in neural disorders, the real-time determination (and manipulation) of error in training, and complex systems that embody planning such as brain machine interfaces, team sports, crowds, or swarms. In addition, observing intent as it changes might act as a window into the mechanisms of planning, correction, and learning.
Physical practice with one hand results in performance gains of the other (un-practiced) hand, yet the role of sensory feedback and underlying neurophysiology is unclear. Healthy subjects learned sequences of finger movements by physical training with their right hand while receiving real-time movement-based visual feedback via 3D virtual reality devices as if their immobile left hand was training. This manipulation resulted in significantly enhanced performance gain with the immobile hand, which was further increased when left-hand fingers were yoked to passively follow right-hand voluntary movements. Neuroimaging data show that, during training with manipulated visual feedback, activity in the left and right superior parietal lobule and their degree of coupling with motor and visual cortex, respectively, correlate with subsequent left-hand performance gain. These results point to a neural network subserving short-term motor skill learning and may have implications for developing new approaches for learning and rehabilitation in patients with unilateral motor deficits.