Abstract The tumor microenvironment (TME) is comprised of non-malignant cells that interact with each other and cancer cells, critically impacting biology. TME complex, understanding it requires simplifying approaches. Here we provide an experimental-mathematical approach to decompose the into small circuits interacting cell types. We find, using female breast single-cell-RNA-sequencing data, a hierarchical network interactions, cancer-associated fibroblasts (CAFs) at top secreting factors...

Article16 July 2020Open Access Transparent process A new model for the HPA axis explains dysregulation of stress hormones on timescale weeks Omer Karin orcid.org/0000-0002-9426-5362 Department Molecular Cell Biology, Weizmann Institute Science, Rehovot, Israel Search more papers by this author Moriya Raz Avichai Tendler Alon Bar Yael Korem Kohanim Tomer Milo Uri Corresponding Author [email protected] orcid.org/0000-0003-1121-5907 Information Karin1, Raz1, Tendler1, Bar1, Kohanim1, Milo1 and...

Many countries have applied lockdown that helped suppress COVID-19, but with devastating economic consequences. Here we propose exit strategies from provide sustainable, albeit reduced, activity. We use mathematical models to show a cyclic schedule of 4-day work and 10-day lockdown, or similar variants, can prevent resurgence the epidemic while providing part-time employment. The cycle pushes reproduction number R below one by reduced exposure time exploiting virus latent period: those...

Significance We provide a dataset of millions hormone tests from medical records that shows seasonality with winter−spring peak in hormones for reproduction, growth, metabolism, and stress adaptation. Together long history studies on human function the indicates that, like other animals, humans may have physiological season basic biological functions. further use specific seasonal phases to suggest model circannual clock animals can keep track seasons, similar spirit circadian keeps time day.

Bipolar disorder (BD) is marked by fluctuating mood states over months to years, often with elevated cortisol levels. Elevated can also trigger episodes. Here, we combine longitudinal hair and measurements mathematical modeling provide a potential mechanistic link between timescales in BD. Using 12 cm samples, representing year of growth, found enhanced year-scale fluctuations whose amplitude averaged 4-fold higher BD (n = 26) participants than controls 59). The proximal 2 correlated recent...

Abstract Elevated cortisol in chronic stress and mood disorders causes morbidity including metabolic cardiovascular diseases. There is therefore interest developing drugs that lower by targeting its endocrine pathway, the hypothalamic–pituitary–adrenal (HPA) axis. However, several promising HPA-modulating have failed to reduce long-term disorders, despite effectiveness other hypercortisolism conditions such as Cushing’s syndrome. The reasons for these failures remain unclear. Here, we use a...

Major depressive disorder (MDD) is the most common psychiatric disorder. It has a complex and heterogeneous etiology. Most treatments take weeks to show effects work well only for fraction of patients. Thus, new concepts are needed understand MDD its dynamics. One strong correlates increased activity dysregulation hypothalamic-pituitary-adrenal (HPA) axis which produces stress hormone cortisol. Existing mathematical models HPA describe operation on scale hours, thus unable explore dynamic...

Cortisol is a major human stress hormone, secreted within minutes of acute stress. also has slower patterns variation: strong circadian rhythm and seasonal rhythm. However, longitudinal cortisol dynamics in healthy individuals over timescales months rarely been studied. Here, we measured 55 participants using 12 cm hair, which provides retrospective measurement one year. Individuals showed (non-seasonal) fluctuations averaging about 22% around their baseline. Fourier analysis reveals...

Abstract 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 origin this dysregulation unclear cannot be explained by current models. To address this, we developed new mathematical model for that incorporates changes total functional mass hormone-secreting glands. are caused which act growth factors glands We find shows property dynamical compensation, where gland...

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 seasons. humans, seasonality remains unclear, due to a lack datasets large enough discern common patterns cover all hormones. Here, we analyze an Israeli health record on 46 million person-years, including millions hormone blood tests. We find clear seasonal patterns: effector peak in winter-spring,...

Abstract Hormones are regulatory molecules that impact physiological functions. Much is known about individual hormones, but general rules connect the logic of different hormone systems limited. In this study, we analyzed a range human using mathematical approach to integrate knowledge on endocrine cells, target tissues and regulation, uncover unifying principles circuits. We find number cells in an gland proportional its tissues, as one single cell serves approximately 2000 cells....

Abstract The tumor microenvironment (TME) is composed of various nonmalignant cell types that interact with each other and cancer cells, impacting all aspects biology. TME complex heterogeneous, thus simplifying systems concepts are needed. Here we provide a tractable experimental system powerful mathematical circuit to identify the main molecular interactions govern composition TME. We focus on two major components - associated fibroblasts (CAFs) macrophages (TAMs), define their verify our...

Many autoimmune diseases show flares in which symptoms erupt and then decline. A prominent example is multiple sclerosis (MS) its relapsing-remitting phase. Mathematical models attempting to capture the have often been oscillatory nature, assuming a regular pattern of symptom flare-ups remissions. However, this fails account for non-periodic nature flares, can appear at seemingly random intervals. Here we propose that resemble excitable dynamics triggered by stochastic events minimal...

Abstract Elevated cortisol causes morbidity in chronic stress and mood disorders, including metabolic cardiovascular diseases. There is therefore interest developing drugs that lower by targeting its endocrine pathway, the hypothalamic-pituitary-adrenal (HPA) axis. Several promising HPA-modulating have, however, failed to long-term disorders such as major depressive disorder despite their effectiveness situations where high caused a tumor (Cushing’s syndrome). Why these not well understood....

Abstract 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 the possible actually occur. Each class uses different regulatory logic to perform specific dynamical such as homeostasis, acute input-output response or adjustable set points. The employ interactions on two timescales: secretion scale...

Bipolar disorder (BD) is a dynamic disease in which mania, depression and mixed states vary on timescale of months to years. BD patients characteristically exhibit elevated levels the hormone cortisol. Persistently cortisol can also cause mood episodes substantial fraction general population. Here we combine longitudinal measurements with mathematical modeling provide potential mechanistic link between timescales moods BD. We use hair measure past cortisol, where each cm corresponds month...

Endocrine glands secrete hormones into the circulation to target distant tissues and regulate their functions. The qualitative relationship between hormone-secreting organs is well established, but a quantitative approach currently limited. Quantification important, as it could allow us study endocrine system using engineering concepts of optimality tradeoffs. In this study, we collected literature data on 24 human secreted from dedicated cells. We find that number cells secreting hormone...

By analysing data from Israeli health records, including millions of hormone blood tests, the authors find peaks during winter−spring in circulating levels all primary hormones involved human growth, stress, metabolism and reproduction. contrast, pituitary-derived regulatory peak summer. This circannual clock impacts on function; endocrine gland masses grow with a timescale months due to trophic effects pituitary hormones, generating feedback circuit natural frequency about year according seasons.

Abstract Background Bipolar disorder (BD) is characterized by episodes of manic, depressive and mixed mood states which have profound effects on the patient's quality life. BD diagnosed followed up clinically using psychiatric assessment, with currently no biomarkers in clinical use for diagnosis or follow-up disorder. One potential biomarker stress hormone cortisol, but this has not been tested comparing cortisol within a cohort people BD. Here we asked whether hair might serve as BD, its...

Abstract Bipolar disorder (BD) is a dynamic disease in which mania, depression and mixed states vary on timescale of months to years. BD patients characteristically exhibit elevated levels the hormone cortisol. Persistently cortisol can also cause mood episodes substantial fraction general population. Although that related cortisol, longitudinal dynamics have rarely been studied. Here we use hair measure past where each cm corresponds month growth. Cortisol was measured 12 samples from...