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Development as a Metabolic Regulator: How Molting Controls Cholesteryl Ester Metabolism in the Somatic Stem Cells of C. elegans Raj Rani1, Or Ben-Hemo1, Benjamin Trabelcy1, Agam Bar1, Hans-Joachim Knölker2, Yoram Gerchman1,3,4, and Amir Sapir1*1Department of Biology and the Environment, Faculty of Natural Sciences, University of Haifa, Oranim, Tivon, 36006 Israel2 Fakultät Chemie, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden, Germany3Institute of Evolution, Faculty of Natural Sciences, University of Haifa, Haifa, Israel4Oranim Academic College, Kiryat Tivon, Israel The metabolism of steroids, such as cholesterol, is critical for mammalian physiology and human health, yet its function in invertebrates remains poorly understood. Using Caenorhabditis elegans, we constructed the first comprehensive homology-based enzymatic atlas of steroid metabolism in invertebrates, identifying 159 candidate genes. We performed a two-dimensional genetic and metabolic screen, knocking down the atlas genes under varying cholesterol conditions to identify those functioning in steroid metabolism. Among the screen hits, we focused on mboa-1, an ortholog of mammalian SOAT1/2 enzymes that synthesize cholesteryl esters from sterols and fatty acids. Surprisingly, mboa-1 knockdown and knockout disrupt hypodermis and cuticle integrity. Consistent with its predicted enzymatic function, bacterially expressed C. elegans MBOA-1 generates cholesteryl esters when supplemented with the steroid 4,3-cholesta and fatty acids. Moreover, 4,3-cholesta—but not steroid hormones—rescued the mboa-1 RNAi phenotype, suggesting a new branch of steroid metabolism in C. elegans. mboa-1 is expressed specifically in the somatic stem cells of C. elegans, the seam cells, which contribute to the hypodermis and cuticle. Expression begins in mid-embryogenesis, persists throughout larval development, but declines sharply in adults. Underscoring its role in cuticle dynamics, mboa-1 expression oscillates with the molting cycle and is regulated by lin-29–mediated heterochronic control during the larval-to-adult transition, a stage when seam cells terminally differentiate. Our functional studies in Clade IV and V nematodes, along with insect expression data, suggest that during evolution, mboa-1 regulation was rewired to support a structural role for cholesteryl esters in cuticle formation, diverging from their primarily metabolic functions in mammals and insects. Our findings reveal how, during evolution, steroid metabolism was repurposed for a novel function in nematodes through the mechanistic reconfiguring of developmental regulation and stem cell biology.

Cancer is a genetic disease that results from accumulation of unfavorable mutations. As soon as genetic and epigenetic modifications associated with these mutations become strong enough, the uncontrolled tumor cell growth is initiated, eventually spreading through healthy tissues. Clarifying the dynamics of initiation is critically important for understanding the mechanisms of cancer. Here we present a new theoretical approach, stimulated by analogy with chemical reactions and other stochastic processes in physics and biology, to evaluate the dynamic processes associated with cancer initiation. It is based on a discrete-state stochastic description of the formation of tumors as a fixation of unfavorable mutations. Thus, the main idea is to map complex processes of cancer initiation into a network of stochastic transitions between specific states of the tissue. Using a first-passage analysis, the probabilities for cancer to appear and the average times before this happens are explicitly calculated. The method is applied for estimating the initiation times from clinical data for 28 different types of cancer. It is found, surprisingly, that the higher probability of cancer to occur does not necessarily lead to the fast starting the cancer. This suggests that both lifetime risks and cancer initiation times must be used to evaluate the possibility of appearance of the cancer tumor.  The similarity of the mechanisms of cancer initiation processes with dynamics of chemical reactions are discussed.  Furthermore, it is shown that the order of mutations might lead to different cancer initiation dynamics, explaining surprising experimental observations that order of mutations can affect the cancer outcome. Our view of cancer initiation as a motion in the effective free-energy landscape provides new insights into the mechanisms of these complex processes. FOR THE LATEST UPDATES AND CONTENT ON SOFT MATTER AND BIOLOGICAL PHYSICS AT THE WEIZMANN, VISIT OUR WEBSITE: https://www.biosoftweizmann.com/    

Probabilistically checkable proofs (PCPs) allow encoding a computation so that it can be quickly verified by only reading a few symbols. Inspired by tree codes (Schulman, STOC'93), we propose tree PCPs; these are PCPs that evolve as the computation progresses so that a proof for time t is obtained by appending a short string to the end of the tree PCP proof for time t-1. At any given time step t, a verifier can make a small number of queries to the entire tree PCP string (constructed thus far) to verify the correctness of the entire computation.

 

We construct tree PCPs for non-deterministic space-s computation, where at time step t, the proof only grows by an additional poly(s,log(t)) bits, and the number of queries made by the verifier to the overall proof is poly(s)*t^epsilon, for an arbitrary constant epsilon > 0.
 

Tree PCPs are well-suited to proving correctness of ongoing computation that unfolds over time.  They may be thought of as an information-theoretic analog of the cryptographic notion of incrementally verifiable computation (Valiant, TCC'08). We show that, in the random oracle model, tree PCPs can be compiled to realize a variant of incrementally verifiable computation where the prover is allowed a small number of queries to a large evolving state. This yields the first construction of (a natural variant of) IVC in the random oracle model.

This is a joint work with Alon Rosen and Ron D. Rothblum.