Intrinsic map dynamics exploration for uncharted effective free-energy landscapes
Eliodoro Chiavazzo, Roberto Covino, Ronald R. Coifman, C. William Gear, Anastasia S. Georgiou, Gerhard Hummer, and Ioannis G. Kevrekidis
Direct simulations explore the dynamics of physical systems at their natural pace. Molecular dynamics (MD) simulations (e.g., of macromolecular folding) extensively revisit typical configurations until rare and interesting transition events occur. Biasing the simulator away from regions already explored can, therefore, drastically accelerate the discovery of features. We propose an enhanced sampling simulation framework, where MD and machine learning adaptively bootstrap each other. Machine learning guides the search for important configurations by processing information from previous explorations. This search proceeds iteratively in an algorithmically orchestrated fashion without advance knowledge of suitable collective variables. Applied to a molecular sensor of lipid saturation in membranes, a helix dissociation pathway not seen in millisecond simulations is discovered at the second iteration. (See pp. E5494–E5503.)
Tetragonal CH3NH3PbI3 is ferroelectric
Yevgeny Rakita, Omri Bar-Elli, Elena Meirzadeh, Hadar Kaslasi, Yagel Peleg, Gary Hodes, Igor Lubomirsky, Dan Oron, David Ehre, and David Cahen
Halide perovskite (HaP) semiconductors are revolutionizing the field of photovoltaic (PV) solar energy conversion by showing remarkable performance of solar cells made with HaPs. “Ferroelectrics” is one frequently suggested reason because it may allow the spatial separation of the flow of electrons from where they were generated (holes). Unlike common, electrically insulating, ferroelectric materials, HaPs [especially tetragonal methylammonium lead triiodide (MAPbI3)] are semiconducting, and to find out whether they are ferroelectric requires an approach that is different from what is done customarily. Using such an approach, we prove that tetragonal MAPbI3 is definitely ferroelectric. What still remains to be seen is whether this ferroelectric nature is important for how MAPbI3-based solar cells operate around room temperature. (See pp. E5504–E5512.)
Triplet–triplet energy transfer in artificial and natural photosynthetic antennas
Junming Ho, Elizabeth Kish, Dalvin D. Méndez-Hernández, Katherine WongCarter, Smitha Pillai, Gerdenis Kodis, Jens Niklas, Oleg G. Poluektov, Devens Gust, Thomas A. Moore, Ana L. Moore, Victor S. Batista, and Bruno Robert
Rapid chlorophyll-to-carotenoid triplet–triplet energy transfer (T-TET) in photosynthetic organisms is crucial to photoprotection from singlet oxygen. Photosynthesis reengineered for increased efficiency will result in increased oxygen levels in the cells, and the need to ensure adequately rapid T-TET will arise. Using a combination of theoretical and experimental studies on artificial and natural carotenoid–chlorophyll complexes, we have identified spectroscopic markers indicative of specific pigment–pigment interactions promoting fast T-TET. These interactions comprise essential design principles necessary for photoprotection in reengineered photosynthesis. Antenna systems from anoxygenic organisms suitably reengineered for photoprotection could be used to gather solar energy in the near infrared, which would markedly increase photosynthetic efficiency by better matching the solar spectrum to water oxidation and CO2 reduction. (See pp. E5513–E5521.)
Materials and processing approaches for foundry-compatible transient electronics
Jan-Kai Chang, Hui Fang, Christopher A. Bower, Enming Song, Xinge Yu, and John A. Rogers
Bioresorbable electronic systems have the potential to create important new categories of technologies, ranging from temporary biomedical implants to environmentally benign, green consumer devices. The results presented here provide a collection of ideas that establish the foundations for a realistic technology of this type, in which state-of-the-art silicon complementary metal-oxide-semiconductor foundries serve as the source of microscale, water-soluble electronic components configured for rapid assembly and electrical interconnection on soft, biocompatible polymer substrates. Demonstrations in various high-performance electronic systems illustrate the concepts, and fundamental studies establish the chemical kinetics and end products of dissolution in aqueous environments. (See pp. E5522–E5529.)
Grc3 programs the essential endoribonuclease Las1 for specific RNA cleavage
Monica C. Pillon, Mack Sobhany, Mario J. Borgnia, Jason G. Williams, and Robin E. Stanley
Ribonucleases are molecular scissors that catalyze the cleavage of RNA phosphodiester bonds and play essential roles in RNA processing and maturation. Precursor ribosomal RNA (rRNA) must be processed by several ribonucleases, including the endonuclease Las1, in a carefully orchestrated manner to generate the mature ribosomal subunits. Las1 is essential for cell viability, and mutations in the mammalian gene have been linked with human disease, underscoring the importance of this enzyme. Here, we show that, on its own, Las1 has weak activity; however, when associated with its binding partner, the polynucleotide kinase Grc3, Las1 is programmed to efficiently cleave pre-rRNA at the C2 site. Together, Grc3 and Las1 assemble into a higher-order complex exquisitely primed for cleavage and phosphorylation of RNA. (See pp. E5530–E5538.)
TraR directly regulates transcription initiation by mimicking the combined effects of the global regulators DksA and ppGpp
Saumya Gopalkrishnan, Wilma Ross, Albert Y. Chen, and Richard L. Gourse
TraR is a 73-amino acid protein encoded in the transfer region operon (tra) of the Escherichia coli conjugative F plasmid. Here we describe evidence for a model in which TraR mimics the combined regulatory activities of the transcription factor DksA and the second messenger ppGpp. By interacting with the residues in RNA polymerase that form a ppGpp binding pocket, we suggest that TraR provides a means for regulating transcription initiation by targeting the secondary channel even under conditions that do not result in induction of ppGpp. TraR-like proteins appear to be ubiquitous in bacteria even in phyla distant from the proteobacteriaceae, in support of the accumulating evidence that very small proteins can have a large impact on bacterial biology. (See pp. E5539–E5548.)
Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation
Michael V. Airola, Prajna Shanbhogue, Achraf A. Shamseddine, Kip E. Guja, Can E. Senkal, Rohan Maini, Nana Bartke, Bill X. Wu, Lina M. Obeid, Miguel Garcia-Diaz, and Yusuf A. Hannun
Ceramide is a bioactive lipid involved in numerous cellular functions and disease states that are critically dependent on its site of generation. nSMase2 generates ceramide at the inner leaflet of the plasma membrane and is a therapeutic target for cancer and neurological disorders. Although much is known about the cellular functions of nSMase2, there is limited insight into the molecular mechanisms regulating its activity. Here we present the crystal structure of nSMase2 and identify the lipid-binding N-terminal domain as an allosteric activation domain. Key to activation is a catalytic motif termed the “DK switch,” whose conformation is allosterically gated. This study reveals one mechanism for nSMase2 regulation by lipids and will help guide structure-based development of nSMase2-targeted therapeutics. (See pp. E5549–E5558.)
Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1
Sergii Shydlovskyi, Anke Y. Zienert, Semra Ince, Christine Dovengerds, Annika Hohendahl, Julia M. Dargazanli, Ailisa Blum, Saskia D. Günther, Nikolay Kladt, Michael Stürzl, Astrid C. Schauss, Miriam Kutsch, Aurélien Roux, Gerrit J. K. Praefcke, and Christian Herrmann
In the human organism, guanylate-binding proteins (GBPs) are involved in antimicrobial and antiviral activity, but the mechanism of GBPs’ action remains poorly understood. We have discovered that binding of a substrate molecule, GTP, to the enzyme triggers the release of an aforemasked lipid anchor, which results in GBP polymerization on the one hand and in the attachment of GBPs to lipid membranes on the other. Thus, membrane binding of GBPs competes with protein polymerization and, furthermore, leads to the membrane tethering, which could play a role in a clearance of engulfed pathogens from the cell. Altogether, our findings give deeper insights into GBPs’ molecular mechanism in the course of pathogen response. (See pp. E5559–E5568.)
Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts
Zhenan Liu, Audrey N. Chang, Frederick Grinnell, Kathleen M. Trybus, Dianna M. Milewicz, James T. Stull, and Kristine E. Kamm
Point mutations in the ACTA2 gene encoding smooth muscle (SM) α-actin cause familial thoracic aortic aneurysms and dissections and predispose to premature coronary artery disease, stroke, and moyamoya disease. Studies on the mechanistic basis of these diseases are partly hampered by inability to collect affected tissues from living patients. Fibroblasts cultured from minimally invasive patient skin biopsies allowed study of ACTA2–R258C mutation-induced derangement in cell growth and interrogation of dysfunctional consequences of the mutation after induction of SM α-actin. Results show that R258C dominantly disrupts cytoskeletal properties attributed to SM α-actin and are consistent with deficiencies in multiple cytoskeletal functions. Information gathered from the patient-derived, cell-based assay strategies described herein has potential to facilitate understanding of disease progression mechanisms. (See pp. E5569–E5578.)
Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding
Seung-Ryoung Jung, Christopher Kushmerick, Jong Bae Seo, Duk-Su Koh, and Bertil Hille
G-protein–coupled receptors (GPCRs) can transmit external signals into the cytoplasm via the activation of G proteins. They also mediate G-protein–independent signaling that uses arrestin to activate an extracellular signal-regulated kinase (ERK) cascade. Using real-time optical measurements, we show that arrestin binds in two modes. Stable binding of arrestin to phosphorylated amino acids in the third intracellular loop of the muscarinic receptor upregulates ERK. Transient binding of arrestin to the unphosphorylated receptor downregulates ERK. Thus, the signaling bias of ERK can be determined by binding modes of arrestin to the receptors. Our results suggest a molecular mechanism for GPCR-arrestin-ERK coupling and pave the way for the development of new therapeutic approaches. (See pp. E5579–E5588.)
Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell
Daniel B. Herrick, Brian Lin, Jesse Peterson, Nikolai Schnittke, and James E. Schwob
Self-renewing tissues require both facultative and injury-activated reserve stem cells to maintain integrity. Horizontal basal cells (HBCs), dormant reserve stem cells of the olfactory epithelium, are roused when tissue damage leads to the suppression of the transcription factor ΔNp63, and regenerate all epithelial cell types, including sensory neurons. We show that the targeted death of the sustentacular cells, but not of neurons, leads to activation. Signaling via Notch1 receptors, possibly driven by Jagged1 on sustentacular cells, holds HBCs dormant by maintaining p63 expression; Notch 2 does not regulate p63 here. In contrast, p63 is suppressed by Notch signaling in skin and other tissues. Understanding p63 regulation in olfactory epithelium may inform efforts to alleviate the age-related decline in olfactory function. (See pp. E5589–E5598.)
The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1
Fraser I. Young, Marc Keruzore, Xinsheng Nan, Nicole Gennet, Eric J. Bellefroid, and Meng Li
Maintaining an intricate balance between continued progenitor proliferation and cell cycle exit/differentiation is pivotal for proper brain development. Disruption of this delicate process can lead to brain malformations, such as microlissencephaly. In this paper, we identify Dmrta2 (doublesex- and mab-3–related transcription factor a2, also known as Dmrt5) as an important transcription factor that helps regulate the fine tuning between cell cycle progression and neuronal differentiation. Mechanistically, this function of Dmrta2 involves direct transcriptional regulation of a known repressor of neurogenesis Hes1. Our findings thus add Dmrta2 to the complex regulatory machinery controlling cortical NPC maintenance, and provide an explanation for the microlissencephaly caused by Dmrta2 deficiency in model organisms and humans. (See pp. E5599–E5607.)
Antagonistic BMP–cWNT signaling in the cnidarian Nematostella vectensis reveals insight into the evolution of mesoderm
Naveen Wijesena, David K. Simmons, and Mark Q. Martindale
Definitive mesoderm (e.g., muscle cells) evolved in the ancestor of the bilateria but is not present in their sister group, Cnidaria. Forward transcriptomics and gene knockdown in the anthozoan Nematostella vectensis show that both cWnt and BMP 2/4 signaling pathways reciprocally regulate components of the endomesodermal gene regulatory network (GRN) during development to set up distinct regional territories prior to the onset of gastrulation. Furthermore, the conserved “kernel” of the bilaterian heart mesoderm GRN is operational in the endomesoderm of the anthozoan N. vectensis. This GRN fails to have a “lockdown” feedback loop found in bilaterian GRNs that may help explain the highly regenerative potential of adult cnidarian endomesoderm, suggesting that the endoderm and mesoderm arose from the bifunctional endomesoderm. (See pp. E5608–E5615.)
Disentangling the effects of selection and loss bias on gene dynamics
Jaime Iranzo, José A. Cuesta, Susanna Manrubia, Mikhail I. Katsnelson, and Eugene V. Koonin
Evolution of microbes is dominated by horizontal gene transfer and the incessant host–parasite arms race that promotes the evolution of diverse antiparasite defense systems. The evolutionary factors governing these processes are complex and difficult to disentangle, but rapidly growing genome databases provide ample material for testing evolutionary models. Rigorous mathematical modeling of evolutionary processes, combined with computer simulation and comparative genomics, allowed us to elucidate the evolutionary regimes of different classes of microbial genes. Only genes involved in key informational and metabolic pathways are subject to strong selection, whereas most of the others are effectively neutral or even burdensome. Mobile genetic elements and defense systems are costly, supporting the understanding that their evolution is governed by the same factors. (See pp. E5616–E5624.)
Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival
Vasilena Gocheva, Alexandra Naba, Arjun Bhutkar, Talia Guardia, Kathryn M. Miller, Carman Man-Chung Li, Talya L. Dayton, Francisco J. Sanchez-Rivera, Caroline Kim-Kiselak, Noor Jailkhani, Monte M. Winslow, Amanda Del Rosario, Richard O. Hynes, and Tyler Jacks
Quantitative mass spectrometric profiling of the extracellular matrix composition of normal lung, fibrotic lung, primary lung tumors, and lung metastases to the lymph nodes uncovered specific signatures distinguishing these tissues. CRISPR/Cas9-mediated gene activation of one of the identified factors, Tenascin-C (Tnc), showed that this protein plays a role in mediating lung adenocarcinoma metastasis. Tnc expression is repressed, directly or indirectly, by the transcription factor Nkx2-1. Bioinformatic analysis shows that expression of three matrisome factors (TNC, S100A10, and S100A11) can predict survival in patients with lung adenocarcinoma. These factors could serve as disease markers that could be exploited for better diagnosis of lung cancer, and their future study could be used to inform the design of more potent treatments for patients. (See pp. E5625–E5634.)
Intact piRNA pathway prevents L1 mobilization in male meiosis
Simon J. Newkirk, Suman Lee, Fiorella C. Grandi, Valeriya Gaysinskaya, James M. Rosser, Nicole Vanden Berg, Cathryn A. Hogarth, Maria C. N. Marchetto, Alysson R. Muotri, Michael D. Griswold, Ping Ye, Alex Bortvin, Fred H. Gage, Jef D. Boeke, and Wenfeng An
Retrotransposons make up the bulk of the human genome and, if unleashed, threaten the genomic integrity through DNA damage and insertional mutagenesis. In germ cells, an intact PIWI-interacting RNA pathway is essential for suppressing the expression of L1 retrotransposons. Deficiencies in the PIWI-interacting RNA pathway have dire consequences because mutant males are invariably sterile. To address the role of retrotransposon activation in these mutants, we developed an L1 reporter transgenic mouse. This mouse model allowed us to detect significant and stage-specific increases of new insertions in mutant germ cells, to draw attention to the importance of other L1-related activities for germ-cell health, and to predict the timing and origin of heritable L1 insertions in the human population. (See pp. E5635–E5644.)
Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules
Alfonso Blázquez-Moreno, Soohyung Park, Wonpil Im, Melissa J. Call, Matthew E. Call, and Hugh T. Reyburn
Many activating immunoreceptors associate, via interactions between transmembrane domains, with adaptor molecules that mediate signaling for leukocyte activation. To date, the best characterized form of receptor complex assembly depends on a single basic transmembrane (TM) domain residue. We now describe a second, completely different solution for TM-mediated receptor assembly, found in three different Fc receptor TM domains, and involving a more complex polar/aromatic interface. Residues in the core of this interaction motif can also regulate receptor protein turnover. Thus, multiple solutions for TM-mediated receptor assembly with signaling modules have evolved. These findings may provide more broadly useful insights into how other immune receptors that do not contain charged residues in their TM domains assemble into complexes with signaling adaptor molecules. (See pp. E5645–E5654.)
Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins
Moustafa R. K. Ali, Yue Wu, Yan Tang, Haopeng Xiao, Kuangcai Chen, Tiegang Han, Ning Fang, Ronghu Wu, and Mostafa A. El-Sayed
Metastasis is the primary cause of cancer-related deaths. Current clinical treatments for antimetastasis, however, are not effective. This work aims to develop a strategy to inhibit cancer cell migration using gold nanorods (AuNRs) with systematic understanding of the mechanism. The ability of targeting AuNRs to cancer cell surface integrins and the introduction of NIR light to generate a mild plasmonic photothermal effect caused broad regulation on cytoskeletal proteins, thus impairing cancer cell migration. This strategy provides a potential application for controlling cancer metastasis. (See pp. E5655–E5663.)
IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts
Jaira F. de Vasconcellos, Laxminath Tumburu, Colleen Byrnes, Y. Terry Lee, Pauline C. Xu, May Li, Antoinette Rabel, Benjamin A. Clarke, Nicholas R. Guydosh, Richard L. Proia, and Jeffery L. Miller
Fetal hemoglobin (HbF) expression is a tissue- and stage-specific marker of ontogeny in large mammals, which also has therapeutic importance for beta hemoglobinopathies. The heterochronic let-7 miRNAs, which regulate the time and sequence of stage-specific developmental events, have also been shown to regulate HbF in adult human erythroblasts. Here we provide a focused investigation of a let-7 target named “insulin-like growth-factor 2 mRNA-binding protein 1” (IGF2BP1), for its potential role in reactivating HbF in adult cells. IGF2BP1 overexpression caused robust increases of HbF and a reversal from the adult toward a fetal-like globin phenotype. IGF2BP1 effects are partially mediated by posttranscriptional regulation of the known HbF regulator BCL11A. These results suggest a novel mechanism for the regulation of BCL11A and HbF in humans. (See pp. E5664–E5672.)
Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk
Rodney M. Ritzel, Anita R. Patel, Monica Spychala, Rajkumar Verma, Joshua Crapser, Edward C. Koellhoffer, Anna Schrecengost, Evan R. Jellison, Liang Zhu, Venugopal Reddy Venna, and Louise D. McCullough
Stroke is an age-related disease that disproportionately affects women. Although experimental studies have identified several hormonal and genetic factors underlying these differences, little is known about how reproductive experience influences risk. This study examined the role of pregnancy and parturition on neurovascular function and behavior in both normal female mice and in females exposed to stroke. We found that reproductive experience increases systemic metabolic risk and results in significant behavioral deficits that are associated with CNS immunosuppression. After stroke, however, multiparous females exhibited smaller infarct volumes, attenuated inflammatory responses, enhanced angiogenesis, and improved behavioral recovery. Although the precise mechanisms underlying this paradoxical finding remain unknown, parity was associated with higher VEGF and improved postischemic vascular remodeling. (See pp. E5673–E5682.)
Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine
Rodrigo Noseda, Alice J. Lee, Rony-Reuven Nir, Carolyn A. Bernstein, Vanessa M. Kainz, Suzanne M. Bertisch, Catherine Buettner, David Borsook, and Rami Burstein
Many migraineurs report that their need to avoid light is driven mainly by how unpleasant it makes them feel. Seeking to understand why light is unpleasant, we show here that light can trigger the perception of chest tightness, shortness of breath, light-headedness, dry mouth, irritability, sadness, and fear (among other aversive symptoms identified), and that these perceptions are mediated by newly described neuronal pathways through which electrical signals generated by light travel from the eye through the hypothalamus to neurons that regulate autonomic functions and emotions. We conclude that the aversive nature of light during migraine is more complex than its association with headache intensification. (See pp. E5683–E5692.)
Simulating tactile signals from the whole hand with millisecond precision
Hannes P. Saal, Benoit P. Delhaye, Brandon C. Rayhaun, and Sliman J. Bensmaia
When we grasp an object, thousands of tactile nerve fibers become activated and inform us about its physical properties (e.g., shape, size, and texture). Although the properties of individual fibers have been described, our understanding of how object information is encoded in populations of fibers remains primitive. To fill this gap, we have developed a simulation of tactile fibers that incorporates much of what is known about skin mechanics and tactile nerve fibers. We show that simulated fibers match biological ones across a wide range of conditions sampled from the literature. We then show how this simulation can reveal previously unknown ways in which populations of nerve fibers cooperate to convey sensory information and discuss the implications for bionic hands. (See pp. E5693–E5702.)
Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease
Rishika Kundra, Prajwal Ciryam, Richard I. Morimoto, Christopher M. Dobson, and Michele Vendruscolo
Alzheimer’s disease is a neurodegenerative disorder whose molecular origins have been associated with the dysregulation of a set of metastable proteins prone to aggregation. Under conditions of cellular and organismal health, the protein homeostasis system prevents effectively the misfolding and aggregation of these metastable proteins. Although it is well established that such regulatory mechanisms become progressively impaired with aging, resulting in an accumulation of protein deposits, the specific nature of such impairment has remained incompletely characterized. Through a gene coexpression analysis, here we identify the endosomal–lysosomal and ubiquitin–proteasome systems, and more generally the protein trafficking and clearance mechanisms, as key components of the protein homeostasis system that maintains the metastable proteins in their functional states. (See pp. E5703–E5711.)
Arabidopsis ABCG34 contributes to defense against necrotrophic pathogens by mediating the secretion of camalexin
Deepa Khare, Hyunju Choi, Sung Un Huh, Barbara Bassin, Jeongsik Kim, Enrico Martinoia, Kee Hoon Sohn, Kyung-Hee Paek, and Youngsook Lee
Alternaria brassicicola infection causes dark spots on the leaves of most Brassica species, reducing the yield of economically important oilseed crops. In response to A. brassicicola infection, Arabidopsis thaliana and other Brassicaceae produce and secrete camalexin, a major phytoalexin imparting resistance to A. brassicicola. Because camalexin is toxic to the plant itself, specific transporters are needed for secretion. Here we show that the ABC transporter ABCG34 mediates the secretion of camalexin from the epidermal cells to the surface of leaves and thereby confers resistance to A. brassicicola infection. This work establishes a complete picture of a plant defense system, consisting of a toxic secondary metabolite, its transporter, and the disease phenotype caused by an economically important pathogen. (See pp. E5712–E5720.)
Phosphosite charge rather than shootward localization determines OCTOPUS activity in root protophloem
Alice S. Breda, Ora Hazak, and Christian S. Hardtke
The evolution of plant vasculature was a key event in earth history because it enabled plants to effectively colonize land. The phloem vasculature was particularly important in this process. In angiosperms, the dominant group of extant terrestrial plants, phloem is assembled from specific conductive cells, the sieve elements. Here we provide evidence that a master regulator of the commitment to sieve element fate in Arabidopsis is strongly conserved and already present in the most basal extant angiosperms. We demonstrate the exquisite dosage-sensitive action of this polar-localized protein and show that its activity is in part regulated through the charge in a phosphorylation site. Surprisingly, however, its shootward polar localization does not appear to be essential for its function. (See pp. E5721–E5730.)
Constrained sampling experiments reveal principles of detection in natural scenes
Stephen Sebastian, Jared Abrams, and Wilson S. Geisler
The visibility of a target object may be affected by the specific properties of the background scene at and near the target’s location, and by how uncertain the observer is (from one occasion to the next) about the values of the background and target properties. An experimental technique was used to measure how several background properties, and uncertainty, affect human detection thresholds for target objects in natural scenes. The thresholds varied in a highly lawful fashion—multidimensional Weber’s law—that is predicted directly from the statistical structure of natural scenes. The results suggest that the neural gain control mechanisms underlying multidimensional Weber’s law evolved because they are optimal for detection in natural scenes under conditions of high uncertainty. (See pp. E5731–E5740.)
System-wide organization of actin cytoskeleton determines organelle transport in hypocotyl plant cells
David Breuer, Jacqueline Nowak, Alexander Ivakov, Marc Somssich, Staffan Persson, and Zoran Nikoloski
In the crowded interior of a cell, diffusion alone is insufficient to master varying transport requirements for cell sustenance and growth. The dynamic actin cytoskeleton is an essential cellular component that provides transport and cytoplasmic streaming in plant cells, but little is known about its system-level organization. Here, we resolve key challenges in understanding system-level actin-based transport. We present an automated image-based, network-driven framework that accurately incorporates both actin cytoskeleton and organelle trafficking. We demonstrate that actin cytoskeleton network properties support efficient transport in both growing and elongated hypocotyl cells. We show that organelle transport can be predicted from the system-wide cellular organization of the actin cytoskeleton. Our framework can be readily applied to investigate cytoskeleton-based transport in other organisms. (See pp. E5741–E5749.)
Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations
JinSeok Park, William R. Holmes, Sung Hoon Lee, Hong-Nam Kim, Deok-Ho Kim, Moon Kyu Kwak, Chiaochun Joanne Wang, Leah Edelstein-Keshet, and Andre Levchenko
Directional cell migration accompanied by cell polarization is key to progression of aggressive cancers, such as melanoma. Cells can display diverse dynamical patterns, with no single mechanism proposed to account for all of them. We show that a simple model predicts the simultaneous presence of random, oscillatory, and persistent dynamic polarization and migration patterns. This mechanism postulates spatially distributed, mechanochemical feedback, coupling the dynamically changing extracellular matrix–cell contacts to the activation of signaling downstream of the Rho-family small GTPases. We validate this mechanism experimentally and use it to explain the transition from a more benign to a more aggressive cell behavior in melanoma progression. This mechanistic analysis framework is general and can be used for diverse stochastic cell migration behaviors in cancer. (See pp. E5750–E5759.)