Sensing of molecules using quantum dynamics
Agostino Migliore, Ron Naaman, and David N. Beratan
We explore (pp. E2419–E2428) the viability of using intrinsically quantum phenomena for molecular sensing. We formulate a theory for coherent sensing by combining the full analytical description of electronic relaxation processes with mass diffusion and charge transport models. This theory produces molecular-scale design criteria for sensors with responses rooted in quantum mechanical coherence phenomena. For example, the sensitivity of the detector can increase with decreased coupling between the molecular binding sites and the sensor substrate. Exploiting quantum properties of the analyte and the sensing element (e.g., electronic affinity, polarizability, etc.) enables enhanced discrimination among multiple analytes.
Heterogeneity of long-history migration explains cultural differences in reports of emotional expressivity and the functions of smiles
Magdalena Rychlowska, Yuri Miyamoto, David Matsumoto, Ursula Hess, Eva Gilboa-Schechtman, Shanmukh Kamble, Hamdi Muluk, Takahiko Masuda, and Paula Marie Niedenthal
In an age of globalization, emotional understanding is the central problem of human interaction. Here (pp. E2429–E2436), we show that historical heterogeneity, or the extent to which a country’s present-day population descends from numerous (vs. few) source countries, predicts cultural variation in norms for emotional expressivity. Reanalysis of cultural display rules from 32 countries reveals that historical heterogeneity is associated with norms favoring greater emotional expressivity. In addition, the results of a study of nine countries show that the belief that smiles signal social bonding motives vs. the negotiation of status in a social hierarchy is predicted by historical heterogeneity as well.
Structure-relaxation mechanism for the response of T4 lysozyme cavity mutants to hydrostatic pressure
Michael T. Lerch, Carlos J. López, Zhongyu Yang, Margaux J. Kreitman, Joseph Horwitz, and Wayne L. Hubbell
High pressure has emerged as a powerful tool for exploring the energy landscape of proteins, but structural origins of the pressure response remain controversial. The results of this study (pp. E2437–E2446) on a cavity mutant of T4 lysozyme (L99A) provide direct evidence for a structure-relaxation mechanism wherein pressure shifts conformational equilibria toward states with alternative packing arrangements that fill cavities or voids in the core. Both structure relaxation and cavity hydration can occur in response to pressure, and which dominates is found to depend on details of the energy landscape. The results also address conflicting views regarding the pressure response of L99A that have recently been published.
Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly
Colleen T. Skau, Sergey V. Plotnikov, Andrew D. Doyle, and Clare M. Waterman
The ability of cells to interact with and remodel their extracellular environment is a critical process in developmental morphogenesis, wound healing, and cancer. How the physical and chemical responses of fibroblasts to the extracellular matrix are integrated across the cell remains a major open question. Previous data has shown a major role for the actin cytoskeleton in coordinating deposition and organization of the extracellular matrix by fibroblasts. Our study (pp. E2447–E2456) examines the role of inverted formin 2 (INF2), a protein known to create new actin filaments, in mediating cellular response to extracellular conditions and control of extracellular matrix remodeling. We find that INF2 is responsible for generating specific actin structures and specialized integrin-based fibrillar adhesions that are required for remodeling of the fibronectin extracellular matrix by fibroblasts.
dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants
Lindsey N. Williams, Lisette Marjavaara, Gary M. Knowels, Eric M. Schultz, Edward J. Fox, Andrei Chabes, and Alan J. Herr
An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy drugs. New therapeutic strategies are needed that target mutator phenotypes directly. Mutator phenotypes due to defects in DNA polymerase ε have been implicated in colorectal and endometrial cancers and may emerge in other cancers during treatment. Here (pp. E2457–E2466), we show in budding yeast that such mutator phenotypes are influenced by the levels of dNTPs, the building blocks of DNA. Lowering dNTP pool levels lessens the mutator phenotypes, whereas increasing dNTP pools accentuates the mutator phenotypes. These findings suggest that mutator phenotypes due to error-prone polymerases may be modulated by treatments that target dNTP pools.
Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity
Tony M. Mertz, Sushma Sharma, Andrei Chabes, and Polina V. Shcherbakova
Mutations affecting replicative DNA polymerases δ (Polδ) and ε (Polε) are linked to sporadic and hereditary colorectal cancer and sporadic endometrial cancer in humans. How these mutations promote the genome instability and tumorigenesis is unclear. Here (pp. E2467–E2476), we deciphered the mechanism of mutagenesis caused by the colon cancer-associated variant Polδ-R696W in a yeast model. It is a previously unappreciated pathway in which erroneous DNA synthesis by Polδ-R696W induces checkpoint-dependent expansion of dNTP pools. The increase in dNTP levels, in turn, causes further dramatic reduction in the fidelity of Polδ-R696W, resulting in more errors and continuous activation of the signaling cascade that keeps the dNTP pools expanded, thus forming a “vicious circle.” This phenomenon may provide insight into the processes shaping the genomes of hypermutated human cancers.
Transcriptome dynamics of developing maize leaves and genomewide prediction of cis elements and their cognate transcription factors
Chun-Ping Yu, Sean Chun-Chang Chen, Yao-Ming Chang, Wen-Yu Liu, Hsin-Hung Lin, Jinn-Jy Lin, Hsiang June Chen, Yu-Ju Lu, Yi-Hsuan Wu, Mei-Yeh Jade Lu, Chen-Hua Lu, Arthur Chun-Chieh Shih, Maurice Sun-Ben Ku, Shin-Han Shiu, Shu-Hsing Wu, and Wen-Hsiung Li
Maize is a major crop and a model plant for studying C4 leaf development. However, its regulatory network of leaf development is poorly understood. We used transcriptomes of developing leaves to study gene-expression dynamics and coexpression to reveal functional transition during maize leaf development. More significantly, we developed methods to predict transcription factor-binding sites (TFBSs) and their cognate transcription factors (TFs) or to use the known Arabidopsis TF–TFBS pairs to predict the maize TF–TFBS pairs. In total, we predicted 1,340 novel TFBSs and 253 new TF–TFBS pairs in maize. Twelve predicted TF–TFBS interactions were validated by functional tests, suggesting that our methods perform well. Our study (pp. E2477–E2486) has significantly expanded our knowledge of the regulatory network of maize leaf development.
IL-33 activates tumor stroma to promote intestinal polyposis
Rebecca L. Maywald, Stephanie K. Doerner, Luca Pastorelli, Carlo De Salvo, Susan M. Benton, Emily P. Dawson, Denise G. Lanza, Nathan A. Berger, Sanford D. Markowitz, Heinz-Josef Lenz, Joseph H. Nadeau, Theresa T. Pizarro, and Jason D. Heaney
Colorectal cancer results from genetic lesions in epithelial cells. However, the tumor microenvironment, which is formed by nonepithelial stromal cells, also plays an important role in this disease. The influence of the microenvironment on tumorigenesis is mediated by paracrine signals between tumor epithelial cells and neighboring stromal cells. We found (pp. E2487–E2496) that expression of interleukin 33 (IL-33), an important mediator of type 2 immunity and wound repair, is induced in epithelial cells of human and mouse intestinal tumors. IL-33 promoted intestinal tumorigenesis in ApcMin/+ mice and activated two stromal cell types, subepithelial myofibroblasts and mast cells, known to mediate intestinal dysplasia. Tumor epithelial cells are proposed to coopt IL-33–mediated immune and wound-healing responses to create a microenvironment favorable to tumorigenesis.
Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level
Toshihide Takeuchi, Mari Suzuki, Nobuhiro Fujikake, H. Akiko Popiel, Hisae Kikuchi, Shiroh Futaki, Keiji Wada, and Yoshitaka Nagai
The heat shock response (HSR), a transcriptional response that up-regulates molecular chaperones upon heat shock, is known to be activated in a cell type-specific manner. Despite such imbalanced HSR upon stress, it is unclear as to how organismal protein homeostasis (proteostasis) is maintained. Here (pp. E2497–E2506), we show that elevated expression of molecular chaperones in cells non-cell autonomously improves proteostasis in other cells. We further show that exosome-mediated secretion and intercellular transmission of chaperones are responsible for this non–cell-autonomous improvement of proteostasis. Our study reveals a molecular mechanism of non–cell-autonomous maintenance of organismal proteostasis that could functionally compensate for the imbalanced HSR among different cells, and also provides a novel physiological function of exosomes that contributes to maintenance of proteostasis.
Metabolic and trophic interactions modulate methane production by Arctic peat microbiota in response to warming
Alexander Tøsdal Tveit, Tim Urich, Peter Frenzel, and Mette Marianne Svenning
Microorganisms are key players in emissions of the greenhouse gas (GHG) methane from anoxic carbon-rich peat soils of the Arctic permafrost region. Although available data and modeling suggest a significant temperature-induced increase of GHG emissions from these regions by the end of this century, the controls of and interactions within the underlying microbial networks are largely unknown. This temperature-gradient study (pp. E2507–E2516) of an Arctic peat soil using integrated omics techniques reveals critical temperatures at which microbial adaptations cause changes in metabolic bottlenecks of anaerobic carbon-degradation pathways. In particular taxonomic shifts within functional guilds at different levels of the carbon degradation cascade enable a fast adaptation of the microbial system resulting in high methane emissions at all temperatures.
Targeting β-arrestin2 in the treatment of l-DOPA–induced dyskinesia in Parkinson’s disease
Nikhil M. Urs, Simone Bido, Sean M. Peterson, Tanya L. Daigle, Caroline E. Bass, Raul R. Gainetdinov, Erwan Bezard, and Marc G. Caron
β-Arrestins are unique proteins that have multiple cellular functions such as G protein-coupled receptor signal desensitization, protein trafficking and signaling molecule scaffolding. Treatment of Parkinson’s disease (PD) motor symptoms by l-3,4-dihydroxyphenylalanine (l-DOPA) has been hampered by abnormal involuntary movements or dyskinetic side effects. The cause of these dyskinesias has been attributed to receptor supersensitivity and uncontrolled neuronal excitability. Here (pp. E2517–E2526) we demonstrate in multiple preclinical models of l-DOPA–induced dyskinesias and PD that expression levels of β-arrestin2 can alter manifestation of these dyskinesias by reducing receptor supersensitivity while maintaining the therapeutic effect of l-DOPA. Thus novel drugs that increase β-arrestin–dependent function at dopamine receptors may be useful in ameliorating PD motor symptoms without inducing dyskinesias.
Functional connectivity arises from a slow rhythmic mechanism
Jingfeng M. Li (李景峰), William J. Bentley, Abraham Z. Snyder, Marcus E. Raichle, and Lawrence H. Snyder
Functional connectivity MRI has revolutionized our understanding of brain architecture. Correlated changes in oxygen levels reveal networks of regions. These networks, each linked to particular functions, are conserved across individuals and species. Normal development, learning, and mental disorders are associated with subtle network changes, providing insight into how brains work. Remarkably, the basis of functional connectivity remains unknown. Although some studies have reported data consistent with an oscillatory process, the leading hypothesis involves emergent, arrhythmic dynamics of complex and distributed networks (the “criticality” hypothesis). By using a new electrode-based technique, we show that functional connectivity is not related to criticality, but instead to specific and potentially localizable oscillatory processes. This finding (pp. E2527–E2535) provides a tool to identify the mechanisms underlying functional connectivity.
Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus
Fernando Benetti, Cristiane Regina Guerino Furini, Jociane de Carvalho Myskiw, Gustavo Provensi, Maria Beatrice Passani, Elisabetta Baldi, Corrado Bucherelli, Leonardo Munari, Ivan Izquierdo, and Patrizio Blandina
Integrity of the brain histaminergic system is necessary for long-term memory (LTM) but not short-term memory of step-down inhibitory avoidance (IA). Histamine depletion in hippocampus or basolateral amygdala (BLA) impairs LTM of that task. Histamine infusion into either structure restores LTM in histamine-depleted rats. The restoring effect in BLA occurs even when hippocampal activity was impaired. Cyclic adenosine monophosphate (cAMP) responsive-element-binding protein phosphorylation correlates anatomically and temporally with histamine-induced memory recall. Thus, histaminergic neurotransmission appears critical to provide the brain with the plasticity necessary for IA through recruitment of alternative circuits. Our findings (pp. E2536–E2542) indicate that the histaminergic system comprises parallel, coordinated pathways that provide compensatory plasticity when one brain structure is compromised.
Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor
Radovan Spurny, Sarah Debaveye, Ana Farinha, Ken Veys, Ann M. Vos, Thomas Gossas, John Atack, Sonia Bertrand, Daniel Bertrand, U. Helena Danielson, Gary Tresadern, and Chris Ulens
In this study (pp. E2543–E2552) we take advantage of a recently described chimera of the α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding protein (AChBP), termed α7-AChBP. To date, more than 70 crystal structures have been determined for AChBP in complex with ligands that occupy the orthosteric binding site. Here, we use an innovative screening strategy to discover molecular fragments that occupy allosteric binding sites. In combination with X-ray crystallography we determine a molecular blueprint of three different allosteric sites in α7-AChBP. Using electrophysiological recordings on the human α7 nAChR we demonstrate that each of the three sites is involved in allosteric modulation of the receptor. Our study contributes to understanding the sites of allosteric binding in ion channels.