PNAS PLUS

PNAS Plus Significance Statements PNAS PLUS

Observation of highly stable and symmetric classical Landau theory of spontaneous symmetry lanthanide octa-boron inverse breaking. A paradigmatic counterexample is decon- sandwich complexes fined criticality, where quantum interference allows Wan-Lu Li, Teng-Teng Chen, Deng-Hui Xing, Xin Chen, for a direct and continuous transition between states Jun Li (李 隽), and Lai-Sheng Wang with distinct symmetry-breaking patterns, a phenom- Lanthanide borides constitute an important class of enon that is classically forbidden. In this work, we materials with wide industrial applications, but clusters extend the scope of deconfined criticality to a case of lanthanide borides have been rarely investigated. It where breaking of a global symmetry coincides with is of great interest to study these nanosystems, which confinement of a local (gauge) symmetry. Using may provide molecular-level understanding of the Monte Carlo simulations, we investigate a lattice re- emergence of new properties and provide insight into alization of this transition. Remarkably, we uncover designing new boride materials. We have produced emergent and enlarged global and gauge symme- lanthanide boride clusters and probed their electronic tries. These findings direct us in constructing a critical − field theory description. (See pp. E6987–E6995.) structure and chemical bonding. Two Ln2B8 clusters are presented, and they are found to possess inverse Diffusion in networks and the virtue sandwich structures. The neutral Ln2B8 complexes are of burstiness found to possess D8h symmetry with strong Ln–B8 bonding. A unique (d–p)δ bond is found to be important Mohammad Akbarpour and Matthew O. Jackson – – for the Ln B8 Ln interactions. The Ln2B8 inverse sand- The contagion of disease and the diffusion of in- wich complexes broaden the structural chemistry of the formation depend on personal contact. People are lanthanide elements and provide insights into bonding not always available to interact with those around in lanthanide boride materials. (See pp. E6972–E6977.) them, and the timing of people’s activities determines whether people have opportunities to meet and 1.1-billion-year-old porphyrins establish a transmit a germ, idea, etc., and ultimately whether marine ecosystem dominated by widespread contagion or diffusion occurs. We show bacterial primary producers that, in a simple model of contagion or diffusion, the N. Gueneli, A. M. McKenna, N. Ohkouchi, C. J. Boreham, greatest levels of spreading occur when there is het- J. Beghin, E. J. Javaux, and J. J. Brocks erogeneity in activity patterns: Some people are ac- The oceans of Earth’smiddleage,1.8–0.8 billion years tive for long periods of time and then inactive for long ago, were devoid of animal-like life. According to one periods, changing their availability only infrequently, hypothesis, the emergence of large, active organisms while other people alternate frequently between be- was restrained by the limited supply of large food par- ing active and inactive. This observation has policy ticles such as algae. Through the discovery of molecular implications for limiting contagious diseases as well fossils of the photopigment chlorophyll in 1.1-billion- as promoting diffusion of information. (See pp. year-old marine sedimentaryrocks,wewereableto E6996–E7004.) quantify the abundance of different phototrophs. The nitrogen isotopic values of the fossil pigments showed Systems genetic analysis of inversion that the oceans were dominated by cyanobacteria, while polymorphisms in the malaria mosquito larger planktonic algae were scarce. This supports the Anopheles gambiae hypothesis that small cells at the base of the food Changde Cheng, John C. Tan, Matthew W. Hahn, chain limited the flow of energy to higher trophic and Nora J. Besansky levels, potentially retarding the emergence of large Chromosomal inversions play an important role in local and complex life. (See pp. E6978–E6986.) adaptation. Strong evidenceexistsofselectionacting on inversions, but the genic targets inside them are Z Confinement transition of 2 gauge theories largely unknown. Here we take a systems genetics ap- coupled to massless fermions: Emergent proach, analyzing two inversion systems implicated in quantum chromodynamics and SO(5) symmetry climatic adaption by Anopheles gambiae.Weprofiled Snir Gazit, Fakher F. Assaad, Subir Sachdev, physiology, behavior, and transcription in four different Ashvin Vishwanath, and Chong Wang karyotypic backgrounds derived from a common pa- Universal properties of quantum (zero-temperature) rental colony. Acclimation to different climatic regimes phase transitions are typically well-described by the resulted in pervasive inversion-driven phenotypic

www.pnas.org/cgi/doi/10.1073/pnas.ss11530 PNAS | July 24, 2018 | vol. 115 | no. 30 | 7657–7661 Downloaded by guest on September 24, 2021 differences whose magnitude and direction depended upon gen- headgroups move through a membrane-exposed hydrophilic der, environment, and epistatic interactions between inversions. groove, as a credit card moves through a card reader. Here we Inversion-affected loci were significantly enriched inside inversions, show that TMEM16 and GPCR scramblases transport lipids with as predicted by local adaptation theory. Drug perturbation sup- very large headgroups, suggesting an out-of-the-groove trans- ported lipid homeostasis and energy balance as inversion-regulated port mechanism. We propose that scramblases locally deform the functions, a finding supported by research on climatic adaptation in membrane to translocate lipids both within and outside multiple systems. (See pp. E7005–E7014.) the groove. (See pp. E7033–E7042.)

Unrestrained markerless trait stacking in Nannochloropsis Hsp70–Bag3 complex is a hub for proteotoxicity-induced gaditana through combined genome editing and signaling that controls protein aggregation marker recycling technologies Anatoli B. Meriin, Arjun Narayanan, Le Meng, Ilya Alexandrov, Xaralabos John Verruto, Kristie Francis, Yingjun Wang, Melisa C. Low, Jessica Varelas, Ibrahim I. Cissé, and Michael Y. Sherman Greiner, Sarah Tacke, Fedor Kuzminov, William Lambert, Jay McCarren, This work dissects how cells monitor failure of proteasomes and Imad Ajjawi, Nicholas Bauman, Ryan Kalb, Gregory Hannum, and Eric R. Moellering trigger signaling responses defining whether cells survive pro- teotoxic stress or undergo apoptosis. The monitoring mechanism Stacking traits in microalgae is limited by a lack of robust genome involves detection of a buildup of abnormal polypeptides re- modification tools and selectable marker availability. This presents a leased from ribosomes. Accordingly, the system simultaneously key hurdle in developing strains for renewable products including monitors effectiveness of several major processes, including biofuels. Here, we overcome these limitations by combining in- protein synthesis, folding, and degradation. A special scaffold ducible Cre recombinase with constitutive Cas9 nuclease expres- complex composed of heat shock protein 70 (Hsp70) and its sion in the industrial strain, Nannochloropsis gaditana.Withthis cofactor Bcl-2–associated athanogene 3 (Bag3) links accumula- system, we demonstrate marker- and reporter-free recapitulation of tion of abnormal polypeptide species with a number of protein an important lipid productivity trait. In addition, we generate a strain kinases involved in various signal-transduction pathways. A star- harboring seven-gene knockouts within the photosystem antennae tling finding is that an Hsp70–Bag3–regulated kinase, LATS1, encoding genes. The combined use of relatively mature (Cre) and regulates very early events of formation of protein aggregates; emerging (CAS9) genome modification technologies can thus ac- thus protein aggregation appears to be a tightly regulated pro- celerate the pace of industrial strain development and facilitate cess rather than the simple collapse of abnormal proteins. (See basic research into functionally redundant gene families. (See pp. pp. E7043–E7052.) E7015–E7022.)

Affinity switching of the LEDGF/p75 IBD interactome is Fully human agonist antibodies to TrkB using autocrine governed by kinase-dependent phosphorylation cell-based selection from a combinatorial antibody library  Subhalakshmi Sharma, Katerina Cermáková, Jan De Rijck, Jonas Spyros Merkouris, Yves-Alain Barde, Kate E. Binley, Nicholas D. Allen, Demeulemeester, Milan Fábry, Sara El Ashkar, Siska Van Belle, Martin Alexey V. Stepanov, Nicholas C. Wu, Geramie Grande, Chih-Wei Lin, Lepsík, Petr Tesina, Vojtech Duchoslav, Petr Novák, Martin Hubálek, Meng Li, Xinsheng Nan, Pedro Chacon-Fernandez, Peter S. DiStefano,  Pavel Srb, Frauke Christ, Pavlína Rezáˇcová, H. Courtney Hodges, Ronald M. Lindsay, Richard A. Lerner, and Jia Xie Zeger Debyser, and Václav Veverka Neurotrophin receptors are a class of receptor tyrosine kinases that The transcription coactivator LEDGF/p75 contributes to regulation couple to signaling pathways critical for neuronal survival and of gene expression by tethering other factors to actively transcribed growth. One member, TrkB, is particularly interesting because it genes on chromatin. Its chromatin-tethering activity is hijacked in plays a role in many severe degenerative neurological diseases. two important disease settings, HIV and mixed-lineage leukemia; The TrkB natural ligand brain-derived neurotrophic factor (BDNF) is however, the basis for the biological regulation of LEDGF/p75’s not suitable to be developed as a drug or therapy as proved by interaction to binding partners has remained unknown. This has previous unsuccessful clinical trials. Here we report a selection represented a gap in our understanding of LEDGF/p75’s funda- method that produced potent full agonist antibodies that mimic mental biological function and a major limitation for development BDNF function, yet with better biophysical properties. This study of therapeutic targeting of LEDGF/p75 in human disease. Our work paves the road for the development of agonist antibodies for other provides a mechanistic understanding of how the lens epithelium- – receptor tyrosine kinases. (See pp. E7023 E7032.) derived growth factor interaction network is regulated at the molecular level. (See pp. E7053–E7062.) Out-of-the-groove transport of lipids by TMEM16 and GPCR scramblases Protein moonlighting elucidates the essential human Mattia Malvezzi, Kiran K. Andra, Kalpana Pandey, Byoung-Cheol Lee, Maria E. Falzone, Ashley Brown, Rabia Iqbal, Anant K. Menon, pathway catalyzing lipoic acid assembly on its and Alessio Accardi cognate enzymes The plasma membrane of all eukaryotic cells is asymmetric, with Xinyun Cao, Lei Zhu, Xuejiao Song, Zhe Hu, and John E. Cronan the signaling lipid phosphatidylserine in the cytoplasmic leaflet. Lipoic acid is an enzyme cofactor found throughout the biological When activated, membrane proteins termed phospholipid world that is required for key steps in central metabolism. In hu- scramblases collapse this asymmetry by exchanging lipids be- mans, defective lipoic acid synthesis results in defective energy tween bilayer leaflets. The resulting externalization of phospha- production, accumulation of toxic levels of certain amino acids, tidylserine is needed for phagocytosis of apoptotic cells, blood and early death. The different pathways for lipoic acid synthesis put coagulation, and membrane repair. The mechanism by which forth have not been validated by direct analysis of the postulated scramblases transport lipids is poorly understood. The struc- enzyme reactions, excepting a protein called LIPT1. Unfortunately, ture of a TMEM16-scramblase suggested that phospholipid the enzyme activity reported for LIPT1 is misleading and seems to

7658 | www.pnas.org/cgi/doi/10.1073/pnas.ss11530 Downloaded by guest on September 24, 2021 be an evolutionary remnant. We report that LIPT1 has a second therapeutic approach to control myopia progression in humans. “moonlighting” enzyme activity that fully explains the physiology (See pp. E7091–E7100.) of individuals lacking LIPT1 activity. We also document the pos- tulated activity of LIPT2, another essential enzyme of the pathway. Polymerization pathway of mammalian nonmuscle (See pp. E7063–E7072.) myosin 2s Xiong Liu, Shi Shu, and Edward D. Korn Solute movement in the t-tubule system of rabbit and Nonmuscle myosin 2 (NM2) filaments are highly dynamic, mouse cardiomyocytes polymerizing and depolymerizing in situ at different cellular Cherrie H. T. Kong, Eva A. Rog-Zielinska, Peter Kohl, Clive H. Orchard, sites where they are essential for multiple functions includ- and Mark B. Cannell ing cell division, cell motility, endocytosis, and exocytosis. Microscopic invaginations of the surface membrane, called Therefore, the mechanism of myosin filament assembly and t-tubules, carry electrical and chemical signals into car- disassembly has high importance. NM2 monomers can be ei- diomyocytes. Previous studies have found slow rates of solute ther folded or unfolded. It has been thought that unfolded exchange inside t-tubules and have suggested that diffusion may monomers and antiparallel bipolar dimers are the fundamen- be highly restricted. By combining fluorescent tracer measure- tal polymerization units. We now show that antiparallel, bi- ments and detailed computational modeling, we show that small polar filaments are formed in vitro by the conversion of ≤ solutes ( 1 kDa) appear to move almost freely within t-tubules folded monomers to folded antiparallel dimers and then an- ∼ – × and most of the 5 16 slowing in exchange rate, compared tiparallel tetramers that unfold, forming bipolar tetramers. with free diffusion, arises from t-tubule geometry effects. Larger Mature filaments consist of multiple unfolded tetramers with > solutes ( 4 kDa) show restricted access into t-tubules, and entwined bare zones. These results should assist our un- species-dependent entry may also be impeded by differences in derstanding of myosin filament dynamics in vivo. (See pp. t-tubule mouth configuration. Our data and analyses provide a E7101–E7108.) new pathway to understanding how disease-induced t-tubule derangement may contribute to altered cellular function. (See GC content elevates mutation and recombination rates – pp. E7073 E7080.) in the yeast Saccharomyces cerevisiae Denis A. Kiktev, Ziwei Sheng, Kirill S. Lobachev, and Thomas D. Petes N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation Chromosomes of most organisms have regions of high GC con- tent interspersed with regions of low GC content. We constructed Laura E. Bowie, Tamara Maiuri, Melanie Alpaugh, Michelle Gabriel, Nicolas Arbez, Danny Galleguillos, Claudia L. K. Hung, Shreya Patel, three variants of the yeast URA3 gene with GC contents of 31%, Jianrun Xia, Nicholas T. Hertz, Christopher A. Ross, David W. Litchfield, 43%, and 63%. We found that the high-GC URA3 gene had a Simonetta Sipione, and Ray Truant substantially elevated rate of mutations, both single-base sub- We have discovered a molecule derived from DNA-damage re- stitutions and deletions. The elevated base substitutions require pair that can correct the lack of phosphorylation of mutant hun- an error-prone DNA polymerase, and the high rate of deletions tingtin, the cause of Huntington’s disease (HD). In a mouse occurs as a consequence of DNA polymerase slippage. The high- model, treatment reverses HD-like disease, and we see the low- GC gene also had substantially elevated rates of mitotic and ering of mutant huntingtin levels to normal. The mechanism of meiotic recombination. These observations indicate that GC this molecule is that it is processed to make a signal for kinase content is an important parameter influencing genome evolution. activity essential for repairing DNA. This mechanism is critical (See pp. E7109–E7118.) when neurons are stressed and have very low or absent energy levels. We propose that this molecule is a type of signaling from Targeting cancer addiction for SALL4 by shifting its DNA-damage repair that occurs at dangerously low ATP levels. transcriptome with a pharmacologic peptide (See pp. E7081–E7090.) Bee Hui Liu, Chacko Jobichen, C. S. Brian Chia, Tim Hon Man Chan, Jing Ping Tang, Theodora X. Y. Chung, Jia Li, Anders Poulsen, Alvin W. Hung, Scleral hypoxia is a target for myopia control Xiaoying Koh-Stenta, Yaw Sing Tan, Chandra S. Verma, Hong Kee Tan, Chan-Shuo Wu, Feng Li, Jeffrey Hill, Joma Joy, Henry Yang, Li Chai, Hao Wu, Wei Chen, Fei Zhao, Qingyi Zhou, Peter S. Reinach, Lili Deng, J. Sivaraman, and Daniel G. Tenen Li Ma, Shumeng Luo, Nethrajeith Srinivasalu, Miaozhen Pan, Yang Hu, Xiaomeng Pei, Jing Sun, Ran Ren, Yinghui Xiong, Zhonglou Zhou, Hepatocellular carcinoma (HCC) is leading cause of death due Sen Zhang, Geng Tian, Jianhuo Fang, Lina Zhang, Jidong Lang, to late discovery and lack of effective treatment. The finding of Deng Wu, Changqing Zeng, Jia Qu, and Xiangtian Zhou the Sal-like 4 (SALL4)–NuRD interaction in HCC opens a new Myopia is the leading cause of visual impairment. Myopic eyes are therapeutic direction targeting an epigenetic regulator. Here, characterized by scleral extracellular matrix (ECM) remodeling, but we identified the SALL4–NuRD binding site through structural the initiators and signaling pathways underlying scleral ECM resolution of the crystal complex, providing valuable insight remodeling in myopia are unknown. In the present study, we found for the development of antagonists against this interaction. that hypoxia-inducible factor-1α (HIF-1α) signaling promoted Our subsequent design of a therapeutic peptide has demon- myopia through myofibroblast transdifferentiation. Furthermore, strated the possibility to develop a first-in-class drug targeting antihypoxic treatments prevented the HIF-1α–associated molec- the SALL4–NuRD interaction in HCC. Furthermore, we dis- ular changes, thus suppressing myopia progression. Our findings covered that the therapeutic peptide exhibits robust antitumor defined the importance of hypoxia in scleral ECM remodeling properties and works by inhibiting the repressive function of and myopia development. The identification of the scleral hyp- SALL4. Our work could also be beneficial to a broad range of oxia in myopia not only provides a concept for understanding the solid cancers and leukemic malignancies with elevated SALL4. mechanisms of myopia development but also suggests viable (See pp. E7119–E7128.)

PNAS | July 24, 2018 | vol. 115 | no. 30 | 7659 Downloaded by guest on September 24, 2021 Different roles of myocardial ROCK1 and ROCK2 in cardiac Rhinovirus induces an anabolic reprogramming in host dysfunction and postcapillary pulmonary hypertension cell metabolism essential for viral replication in mice Guido A. Gualdoni, Katharina A. Mayer, Anna-Maria Kapsch, Katharina Shinichiro Sunamura, Kimio Satoh, Ryo Kurosawa, Tomohiro Ohtsuki, Kreuzberg, Alexander Puck, Philip Kienzl, Felicitas Oberndorfer, Nobuhiro Kikuchi, Md. Elias-Al-Mamun, Toru Shimizu, Shohei Ikeda, Kota Karin Frühwirth, Stefan Winkler, Dieter Blaas, Gerhard J. Zlabinger, Suzuki, Taijyu Satoh, Junichi Omura, Masamichi Nogi, Kazuhiko Numano, and Johannes Stöckl Mohammad Abdul Hai Siddique, Satoshi Miyata, Masahito Miura, Rhinovirus (RV) is the causative agent of the common cold and and Hiroaki Shimokawa other respiratory tract infections. Despite the vast prevalence, Our data suggest opposite roles for ROCK1 and ROCK2 in car- effective treatment or prevention strategies are lacking. Here, we diomyocytes. Additional studies identified downstream targets of analyzed metabolic alterations in infected cells and found a ROCK1 and ROCK2 related to calcium handling, mitochondrial pronounced reprogramming of host cell metabolism toward an function, and oxidative stress. In particular, our findings indicate anabolic state, which involved enhancement of glucose uptake that cyclophilin A (CyPA) and basigin (Bsg), both of which aug- and glycogenolysis. We further demonstrate that these alter- ment oxidative stress, enhanced cardiac dysfunction and post- ations can be reverted by treatment with 2-deoxyglucose, a −/− capillary pulmonary hypertension (PH) in cROCK1 mice, while glycolysis inhibitor, which results in a disruption of RV replication −/− their expressions were lower in cROCK2 mice. Finally, in vitro and in vivo. Thus, we show how the specific metabolic screening of the public chemical library in the Drug Discovery fingerprint of viral infection can be used to generate targets for Initiative enabled us to identify compounds that reduce the ex- antiviral therapy. (See pp. E7158–E7165.) pressions of CyPA and Bsg. Among them, celastrol suppressed the expression of both CyPA and Bsg in heart and lungs, thereby Integration of cell cycle signals by multi-PAS ameliorating both heart failure and postcapillary PH in mice. (See domain kinases pp. E7129–E7138.) Thomas H. Mann and Lucy Shapiro

Superinfection and cure of infected cells as mechanisms for Cells must constantly make decisions involving many pieces hepatitis C virus adaptation and persistence of information at a molecular level. Kinases containing multi- ple PAS sensory domains detect multiple signals to determine Ruian Ke, Hui Li, Shuyi Wang, Wenge Ding, Ruy M. Ribeiro, Elena E. Giorgi, Tanmoy Bhattacharya, Richard J. O. Barnard, Beatrice H. Hahn, their signaling outputs. In the asymmetrically dividing bacterium George M. Shaw, and Alan S. Perelson Caulobacter crescentus, the multisensor proteins DivL and CckA promote different cell types depending upon their subcellular Viral populations exhibit an extraordinary ability to survive abrupt location. We reconstituted the DivL–CckA interaction in vitro and changes in host environment by rapidly generating adaptive mu- showed that specific PAS domains of each protein function to tations. However, our understanding of how viral populations switch CckA between kinase and phosphatase activities, which respond to selection pressure and the underlying molecular reflects their functions in vivo. Within the context of the cell, our mechanisms supporting viral adaptation in vivo is limited. Here, we reconstitution illustrates how multisensor proteins can use their report a set of clinical data sampled from subjects chronically in- subcellular location to regulate their signaling functions. (See pp. fected by hepatitis C virus (HCV). The data show rapid expansion E7166–E7173.) and turnover of drug-resistant viruses following treatment with an HCV protease inhibitor. By fitting mathematical models to the data, we propose that superinfection and cure of infected cells Genome-wide fitness assessment during diurnal growth play critical roles in facilitating the rapid expansion and turn- reveals an expanded role of the cyanobacterial over of viral populations. Our results highlight the importance circadian clock protein KaiA of considering intracellular viral competition in understanding David G. Welkie, Benjamin E. Rubin, Yong-Gang Chang, Spencer rapid viral adaptation. (See pp. E7139–E7148.) Diamond, Scott A. Rifkin, Andy LiWang, and Susan S. Golden Understanding how photosynthetic bacteria respond to and an- Recognition of conserved antigens by Th17 cells provides ticipate natural light–dark cycles is necessary for predictive broad protection against pulmonary Haemophilus modeling, bioengineering, and elucidating metabolic strategies influenzae infection for diurnal growth. Here, we identify the genetic components that – Wenchao Li, Xinyun Zhang, Ying Yang, Qingqin Yin, Yan Wang, Yong Li, are important specifically under light dark cycling conditions and Chuan Wang, Sandy M. Wong, Ying Wang, Howard Goldfine, Brian J. determine how a properly functioning circadian clock prepares Akerley, and Hao Shen metabolism for darkness, a starvation period for photoauto- Nontypeable Haemophilus influenzae (NTHi) is a major cause of trophs. This study establishes that the core circadian clock protein community acquired pneumonia and exacerbation of chronic ob- KaiA is necessary to enable rhythmic derepression of a nighttime structive pulmonary disease. Current effort in NTHi vaccine de- circadian program. (See pp. E7174–E7183.) velopment has focused on generating antibody responses to surface antigens and has had limited success, largely because of Role of sodium channel subtype in action potential antigenic diversity among the numerous circulating NTHi strains. In generation by neocortical pyramidal neurons this study, we have uncovered Th17 responses as the immune Efrat Katz, Ohad Stoler, Anja Scheller, Yana Khrapunsky, Sandra Goebbels, mechanism of cross-protection and identified Th17 antigens Frank Kirchhoff, Michael J. Gutnick, Fred Wolf, and Ilya A. Fleidervish that are conserved and induce protection against NTHi lung Under most conditions cortical pyramidal neurons are strongly bi- infection, thus making a critical first step toward development ased to initiate action potentials in the distal part of the axon initial of a broadly protective “universal” vaccine—the Holy Grail of segment (AIS) rather than in the dendrites, where the excitatory vaccine development against respiratory pathogens. (See pp. postsynaptic potential amplitude is largest. This feature is widely + E7149–E7157.) attributed to the axonal presence of the low-threshold Na channel

7660 | www.pnas.org/cgi/doi/10.1073/pnas.ss11530 Downloaded by guest on September 24, 2021 + subtype Nav1.6. Here, using electrical and high-speed Na imag- occurred in a gradual fashion across the cortical hierarchy and ing recordings from Nav1.6 null pyramidal neurons, we demon- reached an apex in prefrontal cortex. Categorical coding did strate that the presence of this subunit is neither critical for not respect classical models of large-scale cortical organization. positioning the spike initiation site within the AIS nor for the spike The dimensionality of neural population activity was reduced in backpropagation to the dendrites. We also find that one of the parallel with these representational changes. Our results shed + most important features of axonal Na channel kinetics, the lower light on how raw sensory inputs are transformed into behav- + activation threshold, is not entirely dependent on the Na iorally relevant abstractions. (See pp. E7202–E7211.) channel subtype. (See pp. E7184–E7192.) Genetic selection of athletic success in sport-hunting dogs PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and Jaemin Kim, Falina J. Williams, Dayna L. Dreger, Jocelyn Plassais, Brian W. reduces its neuronal protective effect Davis, Heidi G. Parker, and Elaine A. Ostrander Jing He, Mengying Xia, Patrick K. K. Yeung, Jiahua Li, Zhifang Li, Kenny K. We found that hundreds of years of selection by humans have Chung, Sookja K. Chung, and Jun Xia produced sport-hunting breeds of superior speed and athleticism Parkinson’s disease (PD) is the second most common neurode- through strong selection on multiple genes relating to cardio- generative disorder. It is characterized by progressive deteriora- vascular, muscle, and neuronal functions. We further sub- tion of motor function caused by loss of dopamine-producing stantiated these findings by showing that genes under selection neurons. Currently, there is no treatment that could stop the significantly enhanced athleticism, as measured by racing speed progress of the disease. Loss-of-function mutations in Parkin ac- and obstacle course success, using standardized measures from count for ∼50% of early onset PD. Parkin functions as an dogs competing in national competitions. Overall these results E3 ubiquitin ligase that exhibits multiple protective roles espe- reveal both the evolutionary processes and the genetic pathways cially in dopaminergic neurons. Here, we demonstrate that putatively involved in athletic success. (See pp. E7212–E7221.) PICK1 directly binds to Parkin. PICK1 is a potent endogenous inhibitor of Parkin’s E3 ubiquitin ligase activity and blocks Parkin’s Positional specificity of different transcription factor protective functions. Conversely, knockout of PICK1 enhances classes within enhancers the neuroprotective effect of Parkin. Thus, the reduction of Sharon R. Grossman, Jesse Engreitz, John P. Ray, Tung H. Nguyen, PICK1 may provide a therapeutic target for the treatment of PD. Nir Hacohen, and Eric S. Lander – (See pp. E7193 E7201.) Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. The Gradual progression from sensory to task-related degree to which the arrangement of motif sites within regulatory processing in cerebral cortex elements determines their function remains unclear. Here, we Scott L. Brincat, Markus Siegel, Constantin von Nicolai, and Earl K. Miller show that the positional distribution of TF motif sites within The earliest stages of processing in cerebral cortex reflect a rel- nucleosome-depleted regions of DNA fall into six distinct classes. atively faithful copy of sensory inputs, but intelligent behavior These patterns are highly consistent across cell types and bring requires abstracting behaviorally relevant concepts and cate- together factors that have similar functional and binding proper- gories. We examined how this transformation progresses through ties. Furthermore, the position of motif sites appears to be related multiple levels of the cortical hierarchy by comparing neural to their known functions. Our results suggest that TFs play distinct representations in six cortical areas in monkeys categorizing roles in forming a functional enhancer, facilitated by their position across three visual domains. We found that categorical abstraction within a regulatory sequence. (See pp. E7222–E7230.)

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