Bayesian approach to SETI
Claudio Grimaldi and Geoffrey W. Marcy
Ongoing and future initiatives in the search for extraterrestrial intelligence (SETI) will explore the Galaxy on an unprecedented scale to find evidence of communicating civilizations beyond Earth. Here, we construct a Bayesian formulation of SETI to infer the posterior probability of the mean number of radio signals crossing Earth, given a positive or a null outcome of all-sky searches for nonnatural radio emissions. We show that not detecting signals within ∼40 kly from Earth is compatible with the absence in the entire Galaxy of detectable emitters of a wide range of radiated power. The discovery of even a single emission within ∼1 kly implies instead that over 100 signals typically cross our planet from the Milky Way. (See pp. E9755–E9764.)
Education can reduce health differences related to genetic risk of obesity
Silvia H. Barcellos, Leandro S. Carvalho, and Patrick Turley
Educational policies may increase or decrease health differences, depending on whether they reinforce or counteract gene-related differences. We investigate whether one such policy affected health differently for people with different genetic backgrounds. We find that the additional education generated by the policy benefited those with higher genetic risk of obesity the most, reducing the gap in unhealthy body size between those in the top and bottom terciles of genetic risk of obesity from 20 to 6 percentage points. Our results challenge the notion of genetic determinism and underscore the role that social policy can have in mitigating possible health differences arising from genetic background. (See pp. E9765–E9772.)
Tradeoffs in environmental and equity gains from job accessibility
Eleanor C. Stokes and Karen C. Seto
Access to employment is key to the sustainability of urban areas. Although changes in access have consequences for multiple pillars of sustainability, in tandem, potential tradeoffs are rarely explored. This analysis measures employment accessibility trends over the past decade across and within US urban areas and assesses how these trends may be shaping emissions and social equity. We find that although US urban areas have increased in accessibility by 11% on average, few increases have provided both environmental and social value simultaneously. This study points to a paradox in sustainable development, where emissions mitigation and the welfare of low-income urban residents can be at odds. (See pp. E9773–E9781.)
Structural characterization of the D290V mutation site in hnRNPA2 low-complexity–domain polymers
Dylan T. Murray, Xiaoming Zhou, Masato Kato, Siheng Xiang, Robert Tycko, and Steven L. McKnight
Genetic studies have shown that mutations of conserved Asp residues in three analogous heterogeneous ribonucleoproteins are causative of three neurological diseases. All three Asp residues map to domains of low complexity (LC) or intrinsic disorder. These domains form labile self-associated polymers as normal functional states, and the mutations abnormally enhance the stability of the polymers via heretofore unknown mechanisms. The present study gives evidence that the charged Asp residues are closely aligned in the polymer core and removal of electrostatic repulsion enhances polymer stability. These results may provide insight into other neurodegenerative diseases also caused by mutations in LC domains. (See pp. E9782–E9791.)
Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex
Saikat Chowdhury, Chinatsu Otomo, Alexander Leitner, Kazuto Ohashi, Ruedi Aebersold, Gabriel C. Lander, and Takanori Otomo
Autophagosomes are double-membraned compartments that serve a central role in maintaining cellular metabolism and homeostasis. These compartments form de novo adjacent to the endoplasmic reticulum (ER), engulfing cytoplasmic macromolecules and organelles for delivery to lysosomes for recycling. The ER has been thought to supply lipids into the precursor membrane phagophore via the PI3P lipid-enriched membrane unit omegasome, enabling the phagophore to expand for engulfment of a bulk of cytoplasmic materials. We have structurally and biochemically characterized the ATG2A-WIPI4 complex, a factor localized at the omegasome, and show that it forms a rod-shaped structure that can tether PI3P-containing membranes to non–PI3P-containing membranes. Our data suggest that the ATG2A-WIPI4 complex is the long-sought factor that tethers the omegasome to the ER and/or the phagophore. (See pp. E9792–E9801.)
Long noncoding RNA SYISL regulates myogenesis by interacting with polycomb repressive complex 2
Jian Jun Jin, Wei Lv, Pan Xia, Zai Yan Xu, An Dai Zheng, Xiao Jing Wang, Shan Shan Wang, Rui Zeng, Hong Mei Luo, Guo Liang Li, and Bo Zuo
While numerous long noncoding RNAs (lncRNAs) have been identified in muscle, most of their roles in myogenesis remain unclear, and many more lncRNAs have yet to be identified. In this study, we identified an intronic lncRNA, SYISL (SYNPO2 intron sense-overlapping lncRNA), which is highly expressed in muscle and interacts directly with polycomb repressive complex 2 (PRC2) to repress muscle development. The results reveal that SYISL acts as a regulatory RNA in PRC2-mediated myogenesis. (See pp. E9802–E9811.)
Left/right asymmetric collective migration of parapineal cells is mediated by focal FGF signaling activity in leading cells
Myriam Roussigné, Lu Wei, Erika Tsingos, Franz Kuchling, Mansour Alkobtawi, Matina Tsalavouta, Joachim Wittbrodt, Matthias Carl, Patrick Blader, and Stephen W. Wilson
The ability of cells to migrate collectively underlies many biological processes. The parapineal is a small group of cells that requires Fgf8 to migrate from the midline to the left side of the zebrafish forebrain. Studying the dynamics of FGF pathway activation reveals that FGF activity is restricted to a few left-sided parapineal cells. Global activation of the FGF pathway interferes with parapineal migration in wild-type embryos, while focal activation in few parapineal cells can restore migration in fgf8−/− mutants, indicating that FGF pathway activation in leading cells is required for collective migration. We show that focal FGF activity is influenced by left-sided Nodal signaling. Our findings may apply to other contexts of FGF-dependent cell migration during development or metastasis. (See pp. E9812–E9821.)
Serotonin signaling regulates insulin-like peptides for growth, reproduction, and metabolism in the disease vector Aedes aegypti
Lin Ling and Alexander S. Raikhel
Mosquitoes pose an enormous threat to humans by transmitting numerous dangerous diseases. To become reproductively competent and effective disease vectors, it is crucial for them to achieve optimal body size and nutritional status. Elucidation of these processes in mosquitoes has been hampered by the lack of classic genetics tools. CRISPR-Cas9 disruption of the fat-body–specific serotonin receptor Aa5HT2B impairs body growth and lipid accumulation in Aedes aegypti mosquitoes, the vectors of dengue fever, yellow fever, and Zika virus. Aa5HT2B controls insulin-like peptides. Using the CRISPR-Cas9 approach, we have uncovered differential roles of insulin-like peptides in the control of body size and metabolism, and provided a link between blood feeding and the fat-body–specific serotonin signaling. (See pp. E9822–E9831.)
Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
Santosh Kumar, Shubhankar Suman, Albert J. Fornace Jr., and Kamal Datta
Coordinated epithelial cell migration is key to maintaining functional integrity and preventing pathological processes in gastrointestinal tissue, and is essential for astronauts’ health and space mission success. Here we show that energetic heavy ions, which are more prevalent in deep space relative to low-Earth orbit, could persistently decrease intestinal epithelial cell migration, alter cytoskeletal remodeling, and increase cell proliferation with ongoing DNA damage and cell senescence, even a year after irradiation. Our study has provided the molecular underpinnings for energetic heavy-ion 56Fe radiation-induced cell migration alterations, and raises a potentially serious concern, particularly for long-term deep-space manned missions. (See pp. E9832–E9841.)
Neutral and selective dynamics in a synthetic microbial community
Nate J. Cira, Michael T. Pearce, and Stephen R. Quake
We created a synthetic microbial community to help understand how evolution and selection pressure change the species diversity of an ecosystem. Our results show that there is a clear transition between neutral and selective regimes that depends on the rate of immigration as well as the fitness differences. (See pp. E9842–E9848.)
CXCR6+ST2+ memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth
Kazushige Obata-Ninomiya, Kenji Ishiwata, Hisanobu Nakano, Yusuke Endo, Tomomi Ichikawa, Atsushi Onodera, Kiyoshi Hirahara, Yoshitaka Okamoto, Hirotaka Kanuka, and Toshinori Nakayama
Helminth infection elicits T helper type 2 (Th2) and Treg cells. However, the critical cell subpopulations of Th2 and Treg cells in antihelminth immunity remain unknown. We identified two Th2 cell subpopulations: CXCR6+ST2+ memory Th2 cells and ST2− memory Th2 cells. Although both subpopulations induced the accumulation of eosinophils into the lungs during helminth infection, those induced by CXCR6+ST2+ memory Th2 cells expressed high levels of major basic protein (MBP) and contributed to the reduction of fecundity of helminth. This response was suppressed by ST2+ but not ST2− Treg cells, both of which are induced during helminth infection. We, therefore, identified CXCR6+ST2+ memory Th2 cells as a critical subpopulation to induce accumulation of eosinophils strongly expressing MBP in the lungs. (See pp. E9849–E9858.)
Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response
Wenlong Lin, Fasheng Su, Rahul Gautam, Ning Wang, Yuanyuan Zhang, and Xiaojian Wang
Mast cell activation contributes to multiple allergic disorders, such as asthma, rhinitis, and atopic dermatitis. Here, we demonstrate that the Raf kinase inhibitor protein (RKIP) functions as an inhibitor of mast cell activation. RKIP negatively regulates the pathogeneses of the mast cell-mediated anaphylactic response and allergic asthma in vivo. Furthermore, the expression of RKIP was significantly down-regulated in peripheral blood from asthma patients. Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases. (See pp. E9859–E9868.)
Natural molecules induce and synergize to boost expression of the human antimicrobial peptide β-defensin-3
Emmanuel Sechet, Erica Telford, Clément Bonamy, Philippe J. Sansonetti, and Brice Sperandio
Defensins are antimicrobial peptides exhibiting antibacterial, antifungal, and antiviral activity. They are expressed by epithelial cells at the intestinal mucosal surface where they play a crucial role in the host intestinal homeostasis. Therefore, approaches aiming to boost their expression represent a promising therapeutic strategy to treat infections and dysbiosis-driven diseases in humans at a time of increasing incidence of antibiotic resistance. (See pp. E9869–E9878.)
Integrative genomic analysis of mouse and human hepatocellular carcinoma
Michelle Dow, Rachel M. Pyke, Brian Y. Tsui, Ludmil B. Alexandrov, Hayato Nakagawa, Koji Taniguchi, Ekihiro Seki, Olivier Harismendy, Shabnam Shalapour, Michael Karin, Hannah Carter, and Joan Font-Burgada
Hepatocellular carcinoma (HCC) research has been hampered by the absence of consensus mouse models with clearly defined molecular features faithfully recapitulating human HCC. Here we tackle this gap by implementing a cross-species comparative analysis between a large cohort of patients and four diverse mouse models focused on clinically and therapeutically relevant aspects of genomic and transcriptomic profiles and propose two of these models as valid for the study of different stages of human HCC. (See pp. E9879–E9888.)
Role of PDGF receptor-α during human cytomegalovirus entry into fibroblasts
Kai Wu, Adam Oberstein, Wei Wang, and Thomas Shenk
Human CMV (HCMV) is a major cause of birth defects, an opportunistic infection in untreated HIV/AIDS, and a life-threatening complication in immunosuppressed transplant patients. HCMV infects multiple different cell types, so understanding mechanisms supporting the entry of the virus into different cells is crucial to deciphering its pathogenesis. Two viral glycoprotein complexes (trimeric and pentameric complexes) are known to control HCMV tropism in different cell types. Here we have refined our understanding of the mechanism by which the cell-surface receptor tyrosine kinase, PDGF receptor-α, supports the entry of HCMV into fibroblasts. (See pp. E9889–E9898.)
HSP90 is a chaperone for DLK and is required for axon injury signaling
Scott Karney-Grobe, Alexandra Russo, Erin Frey, Jeffrey Milbrandt, and Aaron DiAntonio
Defining mechanisms of axon injury signaling is critical to understand axon regeneration. This knowledge can be used to develop strategies of axonal repair. Identification of such injury signals has been limited by traditional in vivo assays of proregenerative injury signaling. Here, we describe an in vitro screening platform that specifically identifies proregenerative axon injury signals in mouse neurons. We show that HSP90 is required for injury signaling and detail a mechanism by which HSP90 chaperones the essential proregenerative kinase, dual leucine zipper kinase (DLK). Thus, this work also describes HSP90 as a previously unidentified regulator of DLK, a critical neuronal stress sensor that drives axon regeneration, degeneration, and neurological disease. (See pp. E9899–E9908.)
Postnatal TrkB ablation in corticolimbic interneurons induces social dominance in male mice
Shawn Tan, Yixin Xiao, Henry H. Yin, Albert I. Chen, Tuck Wah Soong, and H. Shawn Je
Our ability to reason, feel, and socialize relies on the development of a tight balance between inhibition and excitation within cortical circuits. The growth factor BDNF and its receptor TrkB are important for inhibitory neuron development and have been implicated in neuropsychiatric disorders. However, the behavioral consequences of impaired BDNF/TrkB signaling are unknown. Using a transgenic mouse line, we show that mice with deletion of BDNF/TrkB signaling from cortical inhibitory neurons exhibit social dominance and decreased inhibition within the prefrontal cortex, a key region regulating social behavior. Reversal of the network imbalance with optogenetic inhibition could rescue the behavior. Our results reveal a previously uncharacterized role of growth factor signaling within cortical interneurons for the development of social cognition. (See pp. E9909–E9915.)
NMDA-receptor antibodies alter cortical microcircuit dynamics
Richard E. Rosch, Sukhvir Wright, Gerald Cooray, Margarita Papadopoulou, Sushma Goyal, Ming Lim, Angela Vincent, A. Louise Upton, Torsten Baldeweg, and Karl J. Friston
Recently, autoantibodies against NMDA receptors (NMDARs) were identified as a major cause of autoimmune encephalitis. They cause abnormalities in brain function often associated with significant changes in patients’ brain dynamics. Here we use computational modeling to identify how NMDAR dysfunction causes abnormalities in brain dynamics using patient EEGs and local field potential recordings in a mouse model of NMDAR-Ab encephalitis. NMDAR autoantibodies cause a specific shift in excitatory coupling within cortical circuits that places the circuits closer to pathological transitions between dynamic brain states. Because of the proximity to these phase transitions, otherwise benign fluctuations in neuronal coupling cause abnormal EEG responses in the presence of the antibodies. Our modeling results thus explain fluctuating abnormalities in brain dynamics observed in patients. (See pp. E9916–E9925.)
Adult spinal motoneurons change their neurotransmitter phenotype to control locomotion
Maria Bertuzzi, Weipang Chang, and Konstantinos Ampatzis
An intriguing feature of the nervous system is its plasticity—the remarkable lifelong capacity to change and adapt in light of intrinsic and extrinsic stimuli. Among the many different adaptive mechanisms that occur within the nervous system, changes in neurotransmission form an important plasticity-bestowing mechanism in the reconfiguration of neuronal circuits. Here, we reveal that physical activity and spinal cord injury can switch the neurotransmitter phenotype of the fast axial motoneurons to coexpress glutamate. Furthermore, our study shows that the adult vertebrate spinal motoneurons corelease glutamate alongside ACh in neuromuscular junctions to regulate motor behaviors. Thus, our findings suggest that fast motoneuron glutamatergic respecification enables a motor function-enhancing mechanism in vertebrates. (See pp. E9926–E9933.)
Translocatable voltage-gated Ca2+ channel β subunits in α1–β complexes reveal competitive replacement yet no spontaneous dissociation
Jun-Hee Yeon, Cheon-Gyu Park, Bertil Hille, and Byung-Chang Suh
Voltage-gated Ca2+ (CaV) channels have an α1-α2δ core complexed with one of several alternative β subunits. Contradictory evidence says that, once bound, (i) a β subunit is permanently associated with the α1-α2δ core or (ii) that it is free to be exchanged for other β subunits. We designed rapamycin-translocatable CaV β subunits that allow drug-induced sequestration of free β subunits to several organelle anchors. Sequestering free subunits does not dissociate bound subunits from channels except when the binding site is mutated to weaken the interaction. Nevertheless, our rapamycin constructs show that, when nontranslocatable β subunits are coexpressed with a translocatable subunit, sequestering the translocatable subunit changes the channel properties, revealing a quick replacement by the nontranslocatable subunit in the channel complex. (See pp. E9934–E9943.)
High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing
Cory D. Sago, Melissa P. Lokugamage, Kalina Paunovska, Daryll A. Vanover, Christopher M. Monaco, Nirav N. Shah, Marielena Gamboa Castro, Shannon E. Anderson, Tobi G. Rudoltz, Gwyneth N. Lando, Pooja Mummilal Tiwari, Jonathan L. Kirschman, Nick Willett, Young C. Jang, Philip J. Santangelo, Anton V. Bryksin, and James E. Dahlman
Nanoparticle-mediated delivery of siRNA to hepatocytes has treated disease in humans. However, systemically delivering RNA drugs to nonliver tissues remains an important challenge. To increase the number of nanoparticles that could be studied in vivo, we designed a high-throughput method to measure how >100 nanoparticles delivered mRNA that was translated into functional protein in vivo. We quantified how >250 lipid nanoparticles (LNPs) delivered mRNA in vivo, identifying two LNPs that deliver mRNA to endothelial cells. One of the LNPs codelivered Cas9 mRNA and single-guide RNA in vivo, leading to endothelial cell gene editing. This approach can identify nanoparticles that target new cells. (See pp. E9944–E9952.)
Changes in resource partitioning between and within organs support growth adjustment to neighbor proximity in Brassicaceae seedlings
Mieke de Wit, Gavin M. George, Yetkin Çaka Ince, Barbara Dankwa-Egli, Micha Hersch, Samuel C. Zeeman, and Christian Fankhauser
In dense communities, plants compete for light and sense potentially threatening neighbors prior to actual shading. In response to neighbor proximity cues, shade-intolerant plants selectively elongate stem-like structures, thereby enhancing access to unfiltered sunlight. Although key steps in plant proximity sensing and signaling have been identified, we know little about the metabolic adaptations underlying enhanced stem growth. Here, we show that, following the detection of neighbor proximity cues, seedlings allocate more carbon fixed in the cotyledons to the faster elongating hypocotyl. Moreover, we show that sucrose transport and a transcription factor responding to light and metabolic cues control hypocotyl elongation. Collectively, our work provides important insights into the metabolic changes underlying organ-specific growth adaptations to an environmental stress signal. (See pp. E9953–E9961.)
DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana
Haifeng Zhu, Wenxiang Xie, Dachao Xu, Daisuke Miki, Kai Tang, Chao-Feng Huang, and Jian-Kang Zhu
Genomic imprinting is a form of epigenetic regulation causing parent-of-origin differential expression of maternally or paternally inherited alleles. The DNA demethylase DME regulates the imprinting of many genes in the Arabidopsis endosperm. It is not known whether and how other DNA demethylases may also regulate imprinting. Here, we discovered that the DNA demethylase ROS1 negatively regulates DOGL4 imprinting via demethylation of the DOGL4 promoter on the paternal allele. Additionally, we found that DOGL4 negatively regulates seed dormancy and abscisic acid (ABA) response and that ROS1 regulates seed dormancy and ABA response by controlling DOGL4 expression. Our results thus suggest a different mechanism of regulation of gene imprinting and reveal important roles of ROS1 in the regulation of seed dormancy and ABA response. (See pp. E9962–E9970.)
Abscisic acid-independent stomatal CO2 signal transduction pathway and convergence of CO2 and ABA signaling downstream of OST1 kinase
Po-Kai Hsu, Yohei Takahashi, Shintaro Munemasa, Ebe Merilo, Kristiina Laanemets, Rainer Waadt, Dianne Pater, Hannes Kollist, and Julian I. Schroeder
Elevated CO2 and abscisic acid (ABA) induce rapid stomatal closure, but the underlying signal transduction mechanisms of CO2/ABA interaction remain unclear. Here we show that elevated CO2-induced stomatal closure is not abolished but is slowed in higher-order ABA biosynthesis and receptor mutants. Physiological CO2 elevations activate anion channels in these mutants. In vivo time-resolved ABA nanoreporter imaging indicates that CO2 elevation does not change ABA concentrations in guard cells. Unexpectedly, CO2 signaling proceeds without direct OST1/SnRK2 kinase activation in guard cells. This study points to a model that elevated CO2 triggers stomatal closure through an ABA-independent pathway downstream of OST1/SnRK2 kinases and that basal ABA signaling and OST1/SnRK2 activity enhance stomatal closure in response to CO2 elevation. (See pp. E9971–E9980.)
Converging evidence for functional and structural segregation within the left ventral occipitotemporal cortex in reading
Garikoitz Lerma-Usabiaga, Manuel Carreiras, and Pedro M. Paz-Alonso
Understanding the function, structure, and connections of the ventral occipitotemporal cortex (vOTC) is critical to unravel the neural mechanisms determining how our brain accomplishes reading. Here, we identified two segregated areas along the vOTC posterior–anterior axis involved in two different aspects of visual word recognition: a posterior part responsible for visual feature extraction and an anterior part involved in integrating information from and to the language network. Converging evidence from functional, structural, microarchitectonic, and behavioral measurements consistently confirmed this posterior–anterior segregation in the vOTC and, importantly, revealed the pathways involved in different processes supporting reading. (See pp. E9981–E9990.)