Biology subjects

Tendler, A.

Publications and source records attributed to Tendler, A..

6 recordsLinked to original sources

bioRxiv2024

Unifying regulatory motifs in endocrine circuits

In this study we identify unifying design principles in human endocrine systems. We find that 43 hormone systems, controlling diverse physiological functions, fall into 5 classes of circuits with shared structure - thus only a small number of the possible circuits actually occur. Each class uses a different regulatory logic to perform specific dynamical functions, such as homeostasis, acute input-output response or adjustable set points. The circuits employ interactions on two timescales: hormone secretion on the scale of minutes-hours and growth and shrinkage of endocrine gland mass on the scale of months, which impacts the amount of hormone the glands secrete. This two-timescale principle recurs in several classes of circuits, including the most complex class, which has an intermediate gland, the pituitary. We analyze the pituitary circuit in detail and find tradeoffs between endocrine amplification, buffering of hypersecreting tumors, and rapid response times. These unifying principles of regulation build a foundation for systems endocrinology.

systems biology↗

bioRxiv2023

Unifying design principles of endocrine gland mass and its regulatory circuits

Hormones are regulatory molecules that impact physiological functions. Much is known about individual hormones, but general rules that connect the regulatory logic of different hormone systems are limited. In this study, we analyzed a range of human hormone systems using a mathematical approach to integrate knowledge on endocrine cells, target tissues and regulation, to uncover unifying principles and regulatory circuits. We find that the number of cells in an endocrine gland is proportional to the number of cells in its target tissues, as one single endocrine cell serves approximately 2000 target cells. We identified five classes of regulatory circuits, each has specific regulatory functions such as homeostasis or allostasis. The most complex class includes an intermediate gland, the pituitary, which can otherwise be considered redundant and exposes to fragilities. We suggest a tradeoff: with the price of fragilities comes advantages -amplification, buffering of hypersecreting tumors, and faster response times. By elucidating these unifying principles and circuits, this study deepens our understanding of the control of endocrine processes and builds the foundation for systems endocrinology.

physiology↗

bioRxiv2022

Detailed measurements and simulations of electric field distribution of two TMS coils cleared for obsessive compulsive disorder in the brain and in specific regions associated with OCD

The FDA cleared deep transcranial magnetic stimulation (Deep TMS) with the H7 coil for obsessive-compulsive disorder (OCD) treatment, following a double-blinded placebo-controlled multicenter trial. Two years later the FDA cleared TMS with the D-B80 coil on the basis of substantial equivalence. In order to investigate the induced electric field characteristics of the two coils, these were placed at the treatment position for OCD over the prefrontal cortex of a head phantom, and the field distribution was measured. Additionally, numerical simulations were performed in eight Population Head Model repository models with two sets of conductivity values and three Virtual Population anatomical head models and their homogeneous versions. The H7 was found to induce significantly higher maximal electric fields (p<0.0001, t=11.08) and to stimulate two to five times larger volumes in the brain (p<0.0001, t=6.71). The rate of decay of electric field with distance is significantly slower for the H7 coil (p < 0.0001, Wilcoxon matched-pairs test). The field at the scalp is 306% of the field at a 3 cm depth with the D-B80, and 155% with the H7 coil. The H7 induces significantly higher intensities in broader volumes within the brain and in specific brain regions known to be implicated in OCD (dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC) and pre-supplementary motor area (pre-SMA)) compared to the D-B80. Significant field [≥] 80 V/m is induced by the H7 (D-B80) in 15% (1%) of the dACC, 78% (29%) of the pre-SMA, 50% (20%) of the dlPFC, 30% (12%) of the OFC and 15% (1%) of the IFG. Considering the substantial differences between the two coils, the clinical efficacy in OCD should be tested and verified separately for each coil.

neuroscience↗

bioRxiv2020

Human hormone seasonality

Hormones control the major biological functions of stress response, growth, metabolism and reproduction. In animals these hormones show pronounced seasonality, with different set-points for different seasons. In humans, the seasonality of these hormones remains unclear, due to a lack of datasets large enough to discern common patterns and cover all hormones. Here, we analyze an Israeli health record on 46 million person-years, including millions of hormone blood tests. We find clear seasonal patterns: the effector hormones peak in winter-spring, whereas most of their upstream regulating pituitary hormones peak only months later, in summer. This delay of months is unexpected because known delays in the hormone circuits last hours. We explain the precise delays and amplitudes by proposing and testing a mechanism for the circannual clock: the gland masses grow with a timescale of months due to trophic effects of the hormones, generating a feedback circuit with a natural frequency of about a year that can entrain to the seasons. Thus, humans may show coordinated seasonal set-points with a winter-spring peak in the growth, stress, metabolism and reproduction axes.

systems biology↗

bioRxiv2020

Hormonal dysregulation after prolonged HPA axis activation can be explained by changes of adrenal and corticotroph masses

Stress activates a complex network of hormones known as the Hypothalamic-Pituitary-Adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a new mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by the HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia and postpartum. Dysregulation occurs for a wide range of parameters, and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders. Author SummaryThe HPA axis is a neuroendocrine axis that is activated in response to stressors. The classical description of this axis includes three hormones that act in a cascade, with the final hormone cortisol inhibiting the two upstream hormones, ACTH and CRH. This classical picture has timescales of hours due to hormone half-lives, and cannot explain phenomena on the scale of weeks to months associated with this axis, such as the dysregulation observed in depression, alcohol addiction, postpartum, and other conditions. Here, we use a minimal-model approach to add to the classical model two known interactions in which CRH and ACTH not only regulate downstream hormones, but also act as growth factors for the cells that secrete these hormones. This creates a physiological circuit that can maintain total cell mass and buffer parameter changes. It has a fragility in which after prolonged stress, the total cell functional masses grow and take weeks to return to baseline. This is sufficient to explain the specific dynamics of hormone dysregulation found in several contexts. It also quantifies the effect of the cortisol (glucocorticoid) receptor on resilience to prolonged stress. Our findings suggest that interactions between hormones and cell functional mass may play an important role in HPA axis regulation on the timescale of weeks to months. Synopsis O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY The HPA axis helps the body adapt to stress, but becomes dysregulated after prolonged activation, with clinical consequences. The origin of this dysregulation is unclear. We provide a mechanism for dysregulation based on the effect of the HPA hormones as growth factors for their downstream glands. O_LIA mathematical model that includes gland functional mass dynamics, introduces a new slow timescale of weeks to the HPA axis; previous models had only fast timescales of hours. C_LIO_LIThe gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation. C_LIO_LIThese overshoots are sufficient to explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress. C_LI

physiology↗

bioRxiv2019

Endocrine autoimmune disease as a fragility of immune-surveillance against hypersecreting mutants

Many endocrine organs show prevalent autoimmune diseases (AID) such as type-1-diabetes and Hashimotos-thyroiditis. The fundamental origins of these diseases is unclear. Here we address AID from the viewpoint of feedback control. Endocrine tissues maintain their mass by feedback-loops that balance cell proliferation and removal according to input signals related to the hormone function. Such feedback is unstable to mutant cells that mis-sense the signal, and therefore hyper-proliferate and hyper-secrete the hormone. We hypothesize that in order to prevent these mutants from expanding, each organ has a dedicated autoimmune surveillance of hyper-secreting mutants (ASHM), in which hyper-secreting cells are preferentially eliminated, at the cost of a fragility to AID. ASHM correctly predicts the identity of the self-antigens and the presence of T-cells against these self-antigens in healthy individuals. It offers a predictive theory for which tissues get frequent AID, and which do not and instead show frequent mutant-expansion disease (e.g. hyperparathyroidism).

immunology↗