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  • Molecular pathways to nonbiting mosquitoes
    PNAS (IF 9.661) Pub Date : 2018-01-12
    Peter A. Armbruster

    Mosquitoes are often referred to as the deadliest animals on Earth because of the devastating pathogens they are able to transmit when females bite and then feed on blood from human hosts (male mosquitoes don’t bite). In 2015 alone there were an estimated 212 million cases of malaria, resulting in 429,000 deaths (1). Approximately one-third of Earth’s population is considered at risk for infection by the dengue virus (2). Furthermore, the rapid emergence and global spread of mosquito-borne viruses, such as West Nile, Zika, and chikungunya, are of increasing public health concern (3,4). Because effective vaccines and drug therapies are not available for the majority of these mosquito-borne pathogens, efforts to reduce disease transmission have traditionally focused on suppressing or eliminating the mosquito vector, usually by reducing larval habitats (source reduction) or applying insecticides. However, the effectiveness of these traditional approaches is limited by the proliferation of man-made habitats (e.g., discarded tires and cisterns), the rapid geographic spread of vector species associated with human commerce and travel, and the evolution of insecticide resistance. Novel approaches to control are desperately needed. Recently, a variety of exciting strategies to disrupt disease transmission have emerged based on genetic modification of vectors or infection of vectors with bacterial symbionts (5,6). These strategies seek to either suppress vector populations to sufficiently low numbers that pathogen transmission cannot be sustained (population suppression), or to introduce and spread genetic modifications or bacterial symbiont infections through natural populations so the mosquitoes are incapable of transmitting pathogens (population replacement). Current population replacement strategies focus on preventing the mosquito from transmitting a pathogen once it has already taken a bite and ingested blood. In PNAS, Bradshaw et al. (7) establish the foundation of an intriguing alternative approach based on the potent logic that mosquitoes that don’t …

    更新日期:2018-01-13
  • Greening up the mountain
    PNAS (IF 9.661) Pub Date : 2018-01-12
    V. Vandvik, A. H. Halbritter, R. J. Telford

    The progression of key plant life-history events, such as spring leaf-out and flowering, along bioclimatic gradients in elevation and latitude is one of the more conspicuous patterns in nature, and, as such, it has served as a source of opportunity, industry, inspiration, and wonder for farmers, natural scientists, and artists alike (1⇓–3). For example, in many regions across the world, transhumance, traditional land-use practices that involve the seasonal movement of people and their livestock between fixed summer and winter pastures, has developed to exploit such phenological gradients across the landscape (2,4,5). These phenological patterns are tightly linked to temperature, leading to the formulation of bioclimatic “laws” about phenology (6). Advancing spring phenologies were also among the first clear empirical examples of biotic responses to a warming climate (7,8).

    更新日期:2018-01-13
  • Large genomic insertion at the Shh locus results in hammer toes through enhancer adoption
    PNAS (IF 9.661) Pub Date : 2018-01-12
    Christina Paliou, Guillaume Andrey

    Enhancers arecis-regulatory elements which control the expression of genes in a defined spatiotemporal pattern, enabling the normal morphogenesis of organs and structures during embryogenesis. Enhancers control their target genes independently of their orientation or distance through chromosomal looping and are thought to evolve through various mutational mechanisms (1). A critical biological process that leads to the acquisition of new gene expression domains as well as pathological outcomes is termed “enhancer adoption,” whereby a gene is regulated by an enhancer that is not normally its own (2). Enhancer adoption can derive from the insertion of transposable elements (TEs) with regulatory capacities or genomic structural variants (SVs). In particular, many studies have demonstrated the importance of SVs, including deletions, inversions, duplications, and translocations, with regard to 3D genome organization, gene regulation, and disease (3⇓–5). Recent advances in genome engineering and in sequencing technologies have contributed to a deeper understanding of the molecular mechanisms behind genomic rearrangements and their role in evolution and pathology. Therefore, researchers have seized the opportunity to reinterpret old mouse alleles obtained by spontaneous mutations like X-irradiation-induced phocomelia,Hemimelic extra toes(Hx),Ulnaless, and so on, in the light of modern molecular tools (6⇓–8). In PNAS, Mouri et al. (10) set out to reanalyze a mouse mutant with syndactyly and interdigital webbing, known as Hammer toe (Hm), first described in 1964 (9). The authors found that a genomic insertion of an interdigital regulatory region in the vicinity of the geneSonic hedgehog(Shh) results in its ectopic expression and theHmphenotype. The authors use chromatin technologies and CRISPR/Cas9 genetic engineering to dissect the regulatory function of …

    更新日期:2018-01-13
  • Predicting tipping points in complex environmental systems
    PNAS (IF 9.661) Pub Date : 2018-01-11
    John C. Moore

    Ecologists have long recognized that ecosystems can exist and function in one state within predictable bounds for extended periods of time and then abruptly shift to an alternate state (1⇓⇓⇓–5). Desertification of grasslands, shrub expansion in the Arctic, the eutrophication of lakes, ocean acidification, the formation of marine dead zones, and the degradation of coral reefs represent real and potential ecological regime shifts marked by a tipping point or threshold in one or more external drivers or controlling variables within the system that when breached causes a major change in the system’s structure, function, or dynamics (6⇓⇓–9). Large or incremental alterations in climate, land use, biodiversity (invasive species or the overexploitation of species), and biogeochemical cycles represent external and internal drivers that when pushed too far cross thresholds that can could lead to regime shifts (Fig. 1). Seeing the tipping point after the fact and ascribing mechanisms to the change is one thing; predicting them using empirical data has been a challenge. The difficulty in predicting tipping points stems from the large number of species and interactions (high dimensionality) within ecological systems, the stochastic nature of the systems and their drivers, and the uncertainty and importance of initial conditions that the nonlinear nature of the systems introduce to outcomes. In PNAS, Jiang et al. (10) confront these issues using a dimension-reduction framework that uses empirical data from 59 complex multidimensional plant–pollinator mutualistic networks, some of which contain scores of species and interactions, to develop simpler 2D models for studying and predicting tipping points.

    更新日期:2018-01-12
  • Toward a unifying theory of biodiversity
    PNAS (IF 9.661) Pub Date : 2018-01-11
    Marten Scheffer, Egbert H. van Nes, Remi Vergnon

    Ecologists have long agreed that to coexist species must be sufficiently different (1,2). This worldview was challenged when Stephen Hubbell published his neutral theory of biodiversity showing that species that are essentially equal should also be able to evade competitive exclusion (3). Although this neutral theory inspired a fresh look at biodiversity, it also met resistance as it seemed to violate the deeply held belief that all species are fundamentally different. Interestingly, a harmonious combination of niche differentiation and neutrality can emerge naturally in simulated communities, thus suggesting a way of unifying the niche and neutral view (4). A peculiar prediction of this theory of emergent neutrality is that species should be distributed over niche space in a lumpy way, a pattern that is indeed often observed in nature (5⇓⇓⇓–9). In this view the lumps correspond to niches, while species within lumps are essentially more of the same, reflecting two alternative ways for species to coexist: being sufficiently different or being sufficiently similar (Fig. 1). A study in PNAS now lends important support to this unifying theory by showing its compatibility with Tilman’s widely embraced theory of competition for resources (10).

    更新日期:2018-01-12
  • Partitioning aggression
    PNAS (IF 9.661) Pub Date : 2018-01-11
    Martin Daly

    Have aggression and violence been ramped up in human evolution or dialed down? This sounds like a question that empirical research might have settled long ago, but it remains strangely contentious. In PNAS, Richard Wrangham (1) proposes that debates persist because too many evolutionary anthropologists mistakenly conceive of aggression as unitary and that a well-established distinction between “proactive” and “reactive” aggression holds the key to a resolution.

    更新日期:2018-01-12
  • Future of nonnucleoside reverse transcriptase inhibitors
    PNAS (IF 9.661) Pub Date : 2018-01-11
    Nicolas Sluis-Cremer

    The nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are small molecules that bind to HIV-1 RT at a site distinct from the DNA polymerase active site of the enzyme and block retroviral reverse transcription via an allosteric mechanism of action (1). Nevirapine (NVP) was the first NNRTI approved in 1996 by the US Food and Drug Administration for the treatment of HIV-1 infection, followed by delavirdine in 1997, efavirenz (EFV) in 1998, etravirine (ETV) in 2008, and rilpivirine (RPV) in 2011. For almost 20 y NNRTIs served as the cornerstone of combination antiretroviral therapy (cART). Indeed, most first-line cART included one NNRTI (typically NVP, EFV, or RPV) in combination with two nucleoside/nucleotide RT inhibitors. Just last month, RPV and the integrase inhibitor dolutegravir were approved as the first once-daily, single-pill, two-drug regimen for the maintenance treatment of virologically suppressed HIV-1 infection. ETV can be included in salvage cART for the treatment of HIV-1–infected ART-experienced individuals, including those with prior NNRTI exposure. NNRTIs have also been used to prevent HIV-1 infection. NVP has been used to prevent mother-to-child transmission (2 …

    更新日期:2018-01-12
  • Linked networks for learning and expressing location-specific threat
    PNAS (IF 9.661) Pub Date : 2018-01-11
    Benjamin Suarez-Jimenez, James A. Bisby, Aidan J. Horner, John A. King, Daniel S. Pine, Neil Burgess

    Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were “picked.” Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or “bee sting”); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC–hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula–hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula–dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders.

    更新日期:2018-01-12
  • IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways
    PNAS (IF 9.661) Pub Date : 2018-01-08
    Na-Young Song, Feng Zhu, Zining Wang, Jami Willette-Brown, Sichuan Xi, Zhonghe Sun, Ling Su, Xiaolin Wu, Buyong Ma, Ruth Nussinov, Xiaojun Xia, David S. Schrump, Peter F. Johnson, Michael Karin, Yinling Hu

    Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.

    更新日期:2018-01-11
  • Retraction for Jayandharan et al., Activation of the NF-κB pathway by adeno-associated virus (AAV) vectors and its implications in immune response and gene therapy
    PNAS (IF 9.661) Pub Date : 2018-01-09

    MEDICAL SCIENCESRetraction for “Activation of the NF-κB pathway by adeno-associated virus (AAV) vectors and its implications in immune response and gene therapy,” by Giridhara R. Jayandharan, George Aslanidi, Ashley T. Martino, Stephan C. Jahn, George Q. Perrin, Roland W. Herzog, and Arun Srivastava, which …

    更新日期:2018-01-10
  • Correction for Singh et al., Increasing potential for intense tropical and subtropical thunderstorms under global warming
    PNAS (IF 9.661) Pub Date : 2018-01-09

    EARTH, ATMOSPHERIC, AND PLANETARY SCIENCESCorrection for “Increasing potential for intense tropical and subtropical thunderstorms under global warming,” by Martin S. Singh, Zhiming Kuang, …

    更新日期:2018-01-10
  • Body weight homeostat that regulates fat mass independently of leptin in rats and mice
    PNAS (IF 9.661) Pub Date : 2018-01-09
    John-Olov Jansson, Vilborg Palsdottir, Daniel A. Hägg, Erik Schéle, Suzanne L. Dickson, Fredrik Anesten, Tina Bake, Mikael Montelius, Jakob Bellman, Maria E. Johansson, Roger D. Cone, Daniel J. Drucker, Jianyao Wu, Biljana Aleksic, Anna E. Törnqvist, Klara Sjögren, Jan-Åke Gustafsson, Sara H. Windahl, Claes Ohlsson

    Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass.

    更新日期:2018-01-10
  • Genetic variation interacts with experience to determine interindividual differences in learned song
    PNAS (IF 9.661) Pub Date : 2018-01-09
    David G. Mets, Michael S. Brainard

    Learning reflects the influence of experience on genetically determined circuitry, but little is known about how experience and genetics interact to determine complex learned phenotypes. Here, we used vocal learning in songbirds to study how experience and genetics contribute to interindividual differences in learned song. Previous work has established that such differences in song within a species depend on learning, but in principle some of these differences could also depend on genetic variation. We focused on song tempo, a learned and quantifiable feature that is controlled by central neural circuitry. To identify genetic contributions to tempo we computer-tutored juvenile Bengalese finches (Lonchura striata domestica) from different genetic backgrounds with synthetic songs in which tempo was systematically varied. Computer-tutored birds exhibited unexpectedly strong heritability for song tempo and comparatively weak influence of experience. We then tested whether heritability was fixed and independent of experience by providing a second group of birds with enriched instruction via live social tutoring. Live tutoring resulted in not only a significant increase in the influence of experience on tempo but also a dramatic decrease in the influence of genetics, indicating that enriched instruction could overcome genetic biases evident under computer tutoring. Our results reveal strong heritable genetic contributions to interindividual variation in song tempo but that the degree of heritability depends profoundly on the quality of instruction. They suggest that for more complex learned phenotypes, where it can be difficult to identify and control relevant experiential variables, heritability may similarly be contingent on the specifics of experience.

    更新日期:2018-01-10
  • Generation of a whole-brain atlas for the cholinergic system and mesoscopic projectome analysis of basal forebrain cholinergic neurons
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Xiangning Li, Bin Yu, Qingtao Sun, Yalun Zhang, Miao Ren, Xiaoyan Zhang, Anan Li, Jing Yuan, Linda Madisen, Qingming Luo, Hongkui Zeng, Hui Gong, Zilong Qiu

    The cholinergic system in the brain plays crucial roles in regulating sensory and motor functions as well as cognitive behaviors by modulating neuronal activity. Understanding the organization of the cholinergic system requires a complete map of cholinergic neurons and their axon arborizations throughout the entire brain at the level of single neurons. Here, we report a comprehensive whole-brain atlas of the cholinergic system originating from various cortical and subcortical regions of the mouse brain. Using genetically labeled cholinergic neurons together with whole-brain reconstruction of optical images at 2-μm resolution, we obtained quantification of the number and soma volume of cholinergic neurons in 22 brain areas. Furthermore, by reconstructing the complete axonal arbors of fluorescently labeled single neurons from a subregion of the basal forebrain at 1-μm resolution, we found that their projections to the forebrain and midbrain showed neuronal subgroups with distinct projection specificity and diverse arbor distribution within the same projection area. These results suggest the existence of distinct subtypes of cholinergic neurons that serve different regulatory functions in the brain and illustrate the usefulness of complete reconstruction of neuronal distribution and axon projections at the mesoscopic level.

    更新日期:2018-01-10
  • Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Amanda L. Woerman, Sabeen A. Kazmi, Smita Patel, Atsushi Aoyagi, Abby Oehler, Kartika Widjaja, Daniel A. Mordes, Steven H. Olson, Stanley B. Prusiner

    In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson’s disease (PD), we developed nine α-synuclein−YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T α-synuclein–YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.

    更新日期:2018-01-10
  • Coordinating carbon and nitrogen metabolic signaling through the cyanobacterial global repressor NdhR
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Yong-Liang Jiang, Xue-Ping Wang, Hui Sun, Shu-Jing Han, Wei-Fang Li, Ning Cui, Gui-Ming Lin, Ju-Yuan Zhang, Wang Cheng, Dong-Dong Cao, Zhi-Yong Zhang, Cheng-Cai Zhang, Yuxing Chen, Cong-Zhao Zhou

    The coordination of carbon and nitrogen metabolism is essential for bacteria to adapt to nutritional variations in the environment, but the underlying mechanism remains poorly understood. In autotrophic cyanobacteria, high CO2 levels favor the carboxylase activity of ribulose 1,5 bisphosphate carboxylase/oxygenase (RuBisCO) to produce 3-phosphoglycerate, whereas low CO2 levels promote the oxygenase activity of RuBisCO, leading to 2-phosphoglycolate (2-PG) production. Thus, the 2-PG level is reversely correlated with that of 2-oxoglutarate (2-OG), which accumulates under a high carbon/nitrogen ratio and acts as a nitrogen-starvation signal. The LysR-type transcriptional repressor NAD(P)H dehydrogenase regulator (NdhR) controls the expression of genes related to carbon metabolism. Based on genetic and biochemical studies, we report here that 2-PG is an inducer of NdhR, while 2-OG is a corepressor, as found previously. Furthermore, structural analyses indicate that binding of 2-OG at the interface between the two regulatory domains (RD) allows the NdhR tetramer to adopt a repressor conformation, whereas 2-PG binding to an intradomain cleft of each RD triggers drastic conformational changes leading to the dissociation of NdhR from its target DNA. We further confirmed the effect of 2-PG or 2-OG levels on the transcription of the NdhR regulon. Together with previous findings, we propose that NdhR can sense 2-OG from the Krebs cycle and 2-PG from photorespiration, two key metabolites that function together as indicators of intracellular carbon/nitrogen status, thus representing a fine sensor for the coordination of carbon and nitrogen metabolism in cyanobacteria.

    更新日期:2018-01-10
  • Role of enhanced receptor engagement in the evolution of a pandemic acute hemorrhagic conjunctivitis virus
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Jim Baggen, Daniel L. Hurdiss, Georg Zocher, Nitesh Mistry, Richard W. Roberts, Jasper J. Slager, Hongbo Guo, Arno L. W. van Vliet, Maryam Wahedi, Kimberley Benschop, Erwin Duizer, Cornelis A. M. de Haan, Erik de Vries, José M. Casasnovas, Raoul J. de Groot, Niklas Arnberg, Thilo Stehle, Neil A. Ranson, Hendrik Jan Thibaut, Frank J. M. van Kuppeveld

    Acute hemorrhagic conjunctivitis (AHC) is a painful, contagious eye disease, with millions of cases in the last decades. Coxsackievirus A24 (CV-A24) was not originally associated with human disease, but in 1970 a pathogenic “variant” (CV-A24v) emerged, which is now the main cause of AHC. Initially, this variant circulated only in Southeast Asia, but it later spread worldwide, accounting for numerous AHC outbreaks and two pandemics. While both CV-A24 variant and nonvariant strains still circulate in humans, only variant strains cause AHC for reasons that are yet unknown. Since receptors are important determinants of viral tropism, we set out to map the CV-A24 receptor repertoire and establish whether changes in receptor preference have led to the increased pathogenicity and rapid spread of CV-A24v. Here, we identify ICAM-1 as an essential receptor for both AHC-causing and non-AHC strains. We provide a high-resolution cryo-EM structure of a virus–ICAM-1 complex, which revealed critical ICAM-1–binding residues. These data could help identify a possible conserved mode of receptor engagement among ICAM-1–binding enteroviruses and rhinoviruses. Moreover, we identify a single capsid substitution that has been adopted by all pandemic CV-A24v strains and we reveal that this adaptation enhances the capacity of CV-A24v to bind sialic acid. Our data elucidate the CV-A24v receptor repertoire and point to a role of enhanced receptor engagement in the adaptation to the eye, possibly enabling pandemic spread.

    更新日期:2018-01-10
  • Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Leandro R. Soria, Gabriella Allegri, Dominique Melck, Nunzia Pastore, Patrizia Annunziata, Debora Paris, Elena Polishchuk, Edoardo Nusco, Beat Thöny, Andrea Motta, Johannes Häberle, Andrea Ballabio, Nicola Brunetti-Pierri

    Ammonia is a potent neurotoxin that is detoxified mainly by the urea cycle in the liver. Hyperammonemia is a common complication of a wide variety of both inherited and acquired liver diseases. If not treated early and thoroughly, it results in encephalopathy and death. Here, we found that hepatic autophagy is critically involved in systemic ammonia homeostasis by providing key urea-cycle intermediates and ATP. Hepatic autophagy is triggered in vivo by hyperammonemia through an α-ketoglutarate–dependent inhibition of the mammalian target of rapamycin complex 1, and deficiency of autophagy impairs ammonia detoxification. In contrast, autophagy enhancement by means of hepatic gene transfer of the master regulator of autophagy transcription factor EB or treatments with the autophagy enhancers rapamycin and Tat-Beclin-1 increased ureagenesis and protected against hyperammonemia in a variety of acute and chronic hyperammonemia animal models, including acute liver failure and ornithine transcarbamylase deficiency, the most frequent urea-cycle disorder. In conclusion, hepatic autophagy is an important mechanism for ammonia detoxification because of its support of urea synthesis, and its enhancement has potential for therapy of both primary and secondary causes of hyperammonemia.

    更新日期:2018-01-10
  • Mixed signature of activation and dysfunction allows human decidual CD8+ T cells to provide both tolerance and immunity
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Anita van der Zwan, Kevin Bi, Errol R. Norwitz, Ângela C. Crespo, Frans H. J. Claas, Jack L. Strominger, Tamara Tilburgs

    Understanding how decidual CD8+ T cell (CD8+ dT) cytotoxicity is regulated and how these cells integrate the competing needs for maternal–fetal tolerance and immunity to infection is an important research and clinical goal. Gene-expression analysis of effector-memory CD8+ dT demonstrated a mixed transcriptional signature of T cell dysfunction, activation, and effector function. High protein expression of coinhibitory molecules PD1, CTLA4, and LAG3, accompanied by low expression of cytolytic molecules suggests that the decidual microenvironment reduces CD8+ dT effector responses to maintain tolerance to fetal antigens. However, CD8+ dT degranulated, proliferated, and produced IFN-γ, TNF-α, perforin, and granzymes upon in vitro stimulation, demonstrating that CD8+ dT are not permanently suppressed and retain the capacity to respond to proinflammatory events, such as infections. The balance between transient dysfunction of CD8+ dT that are permissive of placental and fetal development, and reversal of this dysfunctional state, is crucial in understanding the etiology of pregnancy complications and prevention of congenital infections.

    更新日期:2018-01-10
  • Male homosexuality and maternal immune responsivity to the Y-linked protein NLGN4Y
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Anthony F. Bogaert, Malvina N. Skorska, Chao Wang, José Gabrie, Adam J. MacNeil, Mark R. Hoffarth, Doug P. VanderLaan, Kenneth J. Zucker, Ray Blanchard

    We conducted a direct test of an immunological explanation of the finding that gay men have a greater number of older brothers than do heterosexual men. This explanation posits that some mothers develop antibodies against a Y-linked protein important in male brain development, and that this effect becomes increasingly likely with each male gestation, altering brain structures underlying sexual orientation in their later-born sons. Immune assays targeting two Y-linked proteins important in brain development—protocadherin 11 Y-linked (PCDH11Y) and neuroligin 4 Y-linked (NLGN4Y; isoforms 1 and 2)—were developed. Plasma from mothers of sons, about half of whom had a gay son, along with additional controls (women with no sons, men) was analyzed for male protein-specific antibodies. Results indicated women had significantly higher anti-NLGN4Y levels than men. In addition, after statistically controlling for number of pregnancies, mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than did the control samples of women, including mothers of heterosexual sons. The results suggest an association between a maternal immune response to NLGN4Y and subsequent sexual orientation in male offspring.

    更新日期:2018-01-10
  • Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Goo Jun, Alisa Manning, Marcio Almeida, Matthew Zawistowski, Andrew R. Wood, Tanya M. Teslovich, Christian Fuchsberger, Shuang Feng, Pablo Cingolani, Kyle J. Gaulton, Thomas Dyer, Thomas W. Blackwell, Han Chen, Peter S. Chines, Sungkyoung Choi, Claire Churchhouse, Pierre Fontanillas, Ryan King, SungYoung Lee, Stephen E. Lincoln, Vasily Trubetskoy, Mark DePristo, Tasha Fingerlin, Robert Grossman, Jason Grundstad, Alison Heath, Jayoun Kim, Young Jin Kim, Jason Laramie, Jaehoon Lee, Heng Li, Xuanyao Liu, Oren Livne, Adam E. Locke, Julian Maller, Alexander Mazur, Andrew P. Morris, Toni I. Pollin, Derek Ragona, David Reich, Manuel A. Rivas, Laura J. Scott, Xueling Sim, Rick G. Tearle, Yik Ying Teo, Amy L. Williams, Sebastian Zöllner, Joanne E. Curran, Juan Peralta, Beena Akolkar, Graeme I. Bell, Noël P. Burtt, Nancy J. Cox, Jose C. Florez, Craig L. Hanis, Catherine McKeon, Karen L. Mohlke, Mark Seielstad, James G. Wilson, Gil Atzmon, Jennifer E. Below, Josée Dupuis, Dan L. Nicolae, Donna Lehman, Taesung Park, Sungho Won, Robert Sladek, David Altshuler, Mark I. McCarthy, Ravindranath Duggirala, Michael Boehnke, Timothy M. Frayling, Gonçalo R. Abecasis, John Blangero

    A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

    更新日期:2018-01-10
  • Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Bing Chen, Lu Jiang, Meng-Ling Zhong, Jian-Feng Li, Ben-Shang Li, Li-Jun Peng, Yu-Ting Dai, Bo-Wen Cui, Tian-Qi Yan, Wei-Na Zhang, Xiang-Qin Weng, Yin-Yin Xie, Jing Lu, Rui-Bao Ren, Su-Ning Chen, Jian-Da Hu, De-Pei Wu, Zhu Chen, Jing-Yan Tang, Jin-Yan Huang, Jian-Qing Mi, Sai-Juan Chen

    T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up-regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis.

    更新日期:2018-01-10
  • Impact of an historic underground gas well blowout on the current methane chemistry in a shallow groundwater system
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Gilian Schout, Niels Hartog, S. Majid Hassanizadeh, Jasper Griffioen

    Blowouts present a small but genuine risk when drilling into the deep subsurface and can have an immediate and significant impact on the surrounding environment. Nevertheless, studies that document their long-term impact are scarce. In 1965, a catastrophic underground blowout occurred during the drilling of a gas well in The Netherlands, which led to the uncontrolled release of large amounts of natural gas from the reservoir to the surface. In this study, the remaining impact on methane chemistry in the overlying aquifers was investigated. Methane concentrations higher than 10 mg/L (n = 12) were all found to have δ13C-CH4 values larger than −30‰, typical of a thermogenic origin. Both δ13C-CH4 and δD-CH4 correspond to the isotopic composition of the gas reservoir. Based on analysis of local groundwater flow conditions, this methane is not a remnant but most likely the result of ongoing leakage from the reservoir as a result of the blowout. Progressive enrichment of both δ13C-CH4 and δD-CH4 is observed with increasing distance and decreasing methane concentrations. The calculated isotopic fractionation factors of εC = 3 and εD = 54 suggest anaerobic methane oxidation is partly responsible for the observed decrease in concentrations. Elevated dissolved iron and manganese concentrations at the fringe of the methane plume show that oxidation is primarily mediated by the reduction of iron and manganese oxides. Combined, the data reveal the long-term impact that underground gas well blowouts may have on groundwater chemistry, as well as the important role of anaerobic oxidation in controlling the fate of dissolved methane.

    更新日期:2018-01-10
  • Control on rate and pathway of anaerobic organic carbon degradation in the seabed
    PNAS (IF 9.661) Pub Date : 2018-01-09
    F. Beulig, H. Røy, C. Glombitza, B. B. Jørgensen

    The degradation of organic matter in the anoxic seabed proceeds through a complex microbial network in which the terminal steps are dominated by oxidation with sulfate or conversion into methane and CO2. The controls on pathway and rate of the degradation process in different geochemical zones remain elusive. Radiotracer techniques were used to perform measurements of sulfate reduction, methanogenesis, and acetate oxidation with unprecedented sensitivity throughout Holocene sediment columns from the Baltic Sea. We found that degradation rates transition continuously from the sulfate to the methane zone, thereby demonstrating that terminal steps do not exert feedback control on upstream hydrolytic and fermentative processes, as previously suspected. Acetate was a key intermediate for carbon mineralization in both zones. However, acetate was not directly converted into methane. Instead, an additional subterminal step converted acetate to CO2 and reducing equivalents, such as H2, which then fed autotrophic reduction of CO2 to methane.

    更新日期:2018-01-10
  • Field- and clinically derived estimates of Wolbachia-mediated blocking of dengue virus transmission potential in Aedes aegypti mosquitoes
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Lauren B. Carrington, Bich Chau Nguyen Tran, Nhat Thanh Hoang Le, Tai Thi Hue Luong, Truong Thanh Nguyen, Phong Thanh Nguyen, Chau Van Vinh Nguyen, Huong Thi Cam Nguyen, Trung Tuan Vu, Long Thi Vo, Dui Thi Le, Nhu Tuyet Vu, Giang Thi Nguyen, Hung Quoc Luu, Anh Duc Dang, Timothy P. Hurst, Scott L. O’Neill, Vi Thuy Tran, Duong Thi Hue Kien, Nguyet Minh Nguyen, Marcel Wolbers, Bridget Wills, Cameron P. Simmons

    The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, we report that wMel-infected Ae. aegypti (Ho Chi Minh City background), when directly blood-fed on 141 viremic dengue patients, have lower dengue virus (DENV) transmission potential and have a longer extrinsic incubation period than their wild-type counterparts. The wMel-infected mosquitoes that are field-reared have even greater relative resistance to DENV infection when fed on patient-derived viremic blood meals. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. Collectively, these field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti-born arboviruses.

    更新日期:2018-01-10
  • Causes and consequences of decreasing atmospheric organic aerosol in the United States
    PNAS (IF 9.661) Pub Date : 2018-01-09
    D. A. Ridley, C. L. Heald, K. J. Ridley, J. H. Kroll

    Exposure to atmospheric particulate matter (PM) exacerbates respiratory and cardiovascular conditions and is a leading source of premature mortality globally. Organic aerosol contributes a significant fraction of PM in the United States. Here, using surface observations between 1990 and 2012, we show that organic carbon has declined dramatically across the entire United States by 25–50%; accounting for more than 30% of the US-wide decline in PM. The decline is in contrast with the increasing organic aerosol due to wildfires and no clear trend in biogenic emissions. By developing a carbonaceous emissions database for the United States, we show that at least two-thirds of the decline in organic aerosol can be explained by changes in anthropogenic emissions, primarily from vehicle emissions and residential fuel burning. We estimate that the decrease in anthropogenic organic aerosol is responsible for averting 180,000 (117,000–389,000) premature deaths between 1990 and 2012. The unexpected decrease in organic aerosol, likely a consequence of the implementation of Clean Air Act Amendments, results in 84,000 (30,000–164,000) more lives saved than anticipated by the EPA between 2000 and 2010.

    更新日期:2018-01-10
  • Neural induction by the node and placode induction by head mesoderm share an initial state resembling neural plate border and ES cells
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Katherine E. Trevers, Ravindra S. Prajapati, Mark Hintze, Matthew J. Stower, Anna C. Strobl, Monica Tambalo, Ramya Ranganathan, Natalia Moncaut, Mohsin A. F. Khan, Claudio D. Stern, Andrea Streit

    Around the time of gastrulation in higher vertebrate embryos, inductive interactions direct cells to form central nervous system (neural plate) or sensory placodes. Grafts of different tissues into the periphery of a chicken embryo elicit different responses: Hensen’s node induces a neural plate whereas the head mesoderm induces placodes. How different are these processes? Transcriptome analysis in time course reveals that both processes start by induction of a common set of genes, which later diverge. These genes are remarkably similar to those induced by an extraembryonic tissue, the hypoblast, and are normally expressed in the pregastrulation stage epiblast. Explants of this epiblast grown in the absence of further signals develop as neural plate border derivatives and eventually express lens markers. We designate this state as “preborder”; its transcriptome resembles embryonic stem cells. Finally, using sequential transplantation experiments, we show that the node, head mesoderm, and hypoblast are interchangeable to begin any of these inductions while the final outcome depends on the tissue emitting the later signals.

    更新日期:2018-01-10
  • Single-molecule FRET studies on the cotranscriptional folding of a thiamine pyrophosphate riboswitch
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Heesoo Uhm, Wooyoung Kang, Kook Sun Ha, Changwon Kang, Sungchul Hohng

    Because RNAs fold as they are being synthesized, their transcription rate can affect their folding. Here, we report the results of single-molecule fluorescence studies that characterize the ligand-dependent cotranscriptional folding of the Escherichia coli thiM riboswitch that regulates translation. We found that the riboswitch aptamer folds into the “off” conformation independent of its ligand, but switches to the “on” conformation during transcriptional pausing near the translational start codon. Ligand binding maintains the riboswitch in the off conformation during transcriptional pauses. We expect our assay will permit the controlled study of the two main physical mechanisms that regulate cotranscriptional folding: transcriptional pausing and transcriptional speed.

    更新日期:2018-01-10
  • Low-lying excited states in crystalline perylene
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Tonatiuh Rangel, Andre Rinn, Sahar Sharifzadeh, Felipe H. da Jornada, André Pick, Steven G. Louie, Gregor Witte, Leeor Kronik, Jeffrey B. Neaton, Sangam Chatterjee

    Organic materials are promising candidates for advanced optoelectronics and are used in light-emitting diodes and photovoltaics. However, the underlying mechanisms allowing the formation of excited states responsible for device functionality, such as exciton generation and charge separation, are insufficiently understood. This is partly due to the wide range of existing crystalline polymorphs depending on sample preparation conditions. Here, we determine the linear optical response of thin-film single-crystal perylene samples of distinct polymorphs in transmission and reflection geometries. The sample quality allows for unprecedented high-resolution spectroscopy, which offers an ideal opportunity for judicious comparison between theory and experiment. Excellent agreement with first-principles calculations for the absorption based on the GW plus Bethe–Salpeter equation (GW-BSE) approach of many-body perturbation theory (MBPT) is obtained, from which a clear picture of the low-lying excitations in perylene emerges, including evidence of an exciton–polariton stopband, as well as an assessment of the commonly used Tamm–Dancoff approximation to the GW-BSE approach. Our findings on this well-controlled system can guide understanding and development of advanced molecular solids and functionalization for applications.

    更新日期:2018-01-10
  • CO2 reduction to acetate in mixtures of ultrasmall (Cu)n,(Ag)m bimetallic nanoparticles
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Ying Wang, Degao Wang, Christopher J. Dares, Seth L. Marquard, Matthew V. Sheridan, Thomas J. Meyer

    Monodispersed mixtures of 6-nm Cu and Ag nanoparticles were prepared by electrochemical reduction on electrochemically polymerized poly-Fe(vbpy)3(PF6)2 film electrodes on glassy carbon. Conversion of the complex to poly-Fe(vbpy)2(CN)2 followed by surface binding of salts of the cations and electrochemical reduction gave a mixture of chemically distinct clusters on the surface, (Cu)m,(Ag)n|polymer|glassy carbon electrode (GCE), as shown by X-ray photoelectron spectroscopy (XPS) measurements. A (Cu)2,(Ag)3|(80-monolayer-poly-Fe(vbpy)32+|GCE electrode at −1.33 V vs. reversible hydrogen electrode (RHE) in 0.5 M KHCO3, with 8 ppm added benzotriazole (BTA) at 0 °C, gave acetate with a faradaic efficiency of 21.2%.

    更新日期:2018-01-10
  • SbcC-SbcD and ExoI process convergent forks to complete chromosome replication
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Brian M. Wendel, Jessica M. Cole, Charmain T. Courcelle, Justin Courcelle

    SbcC-SbcD are the bacterial orthologs of Mre11-Rad50, a nuclease complex essential for genome stability, normal development, and viability in mammals. In vitro, these enzymes degrade long DNA palindromic structures. When inactivated along with ExoI in Escherichia coli, or Sae2 in eukaryotes, palindromic amplifications arise and propagate in cells. However, long DNA palindromes are not normally found in bacterial or human genomes, leaving the cellular substrates and function of these enzymes unknown. Here, we show that during the completion of DNA replication, convergent replication forks form a palindrome-like structural intermediate that requires nucleolytic processing by SbcC-SbcD and ExoI before chromosome replication can be completed. Inactivation of these nucleases prevents completion from occurring, and under these conditions, cells maintain viability by shunting the reaction through an aberrant recombinational pathway that leads to amplifications and instability in this region. The results identify replication completion as an event critical to maintain genome integrity and cell viability, demonstrate SbcC-SbcD-ExoI acts before RecBCD and is required to initiate the completion reaction, and reveal how defects in completion result in genomic instability.

    更新日期:2018-01-10
  • Visualizing long-term single-molecule dynamics in vivo by stochastic protein labeling
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Hui Liu, Peng Dong, Maria S. Ioannou, Li Li, Jamien Shea, H. Amalia Pasolli, Jonathan B. Grimm, Patricia K. Rivlin, Luke D. Lavis, Minoru Koyama, Zhe Liu

    Our ability to unambiguously image and track individual molecules in live cells is limited by packing of multiple copies of labeled molecules within the resolution limit. Here we devise a universal genetic strategy to precisely control copy number of fluorescently labeled molecules in a cell. This system has a dynamic range of ∼10,000-fold, enabling sparse labeling of proteins expressed at different abundance levels. Combined with photostable labels, this system extends the duration of automated single-molecule tracking by two orders of magnitude. We demonstrate long-term imaging of synaptic vesicle dynamics in cultured neurons as well as in intact zebrafish. We found axon initial segment utilizes a “waterfall” mechanism gating synaptic vesicle transport polarity by promoting anterograde transport processivity. Long-time observation also reveals that transcription factor hops between clustered binding sites in spatially restricted subnuclear regions, suggesting that topological structures in the nucleus shape local gene activities by a sequestering mechanism. This strategy thus greatly expands the spatiotemporal length scales of live-cell single-molecule measurements, enabling new experiments to quantitatively understand complex control of molecular dynamics in vivo.

    更新日期:2018-01-10
  • A growing microcolony can survive and support persistent propagation of virulent phages
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Rasmus Skytte Eriksen, Sine L. Svenningsen, Kim Sneppen, Namiko Mitarai

    Bacteria form colonies and secrete extracellular polymeric substances that surround the individual cells. These spatial structures are often associated with collaboration and quorum sensing between the bacteria. Here we investigate the mutual protection provided by spherical growth of a monoclonal colony during exposure to phages that proliferate on its surface. As a proof of concept we exposed growing colonies of Escherichia coli to a virulent mutant of phage P1. When the colony consists of less than ∼50,000 members it is eliminated, while larger initial colonies allow long-term survival of both phage-resistant mutants and, importantly, colonies of mostly phage-sensitive members. A mathematical model predicts that colonies formed solely by phage-sensitive bacteria can survive because the growth of bacteria throughout the colony exceeds the killing of bacteria on the surface and pinpoints how the critical colony size depends on key parameters in the phage infection cycle.

    更新日期:2018-01-10
  • Structural basis of the phosphorylation-independent recognition of cyclin D1 by the SCFFBXO31 ubiquitin ligase
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Yunfeng Li, Kai Jin, Eric Bunker, Xiaojuan Zhang, Xuemei Luo, Xuedong Liu, Bing Hao

    Ubiquitin-dependent proteolysis of cyclin D1 is associated with normal and tumor cell proliferation and survival. The SCFFBXO31 (Skp1–Cul1–Rbx1–FBXO31) ubiquitin ligase complex mediates genotoxic stress-induced cyclin D1 degradation. Previous studies have suggested that cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and subsequent proteolysis in the cytoplasm. Here we present the crystal structures of the Skp1–FBXO31 complex alone and bound to a phosphorylated cyclin D1 C-terminal peptide. FBXO31 possesses a unique substrate-binding domain consisting of two β-barrel motifs, whereas cyclin D1 binds to FBXO31 by tucking its free C-terminal carboxylate tail into an open cavity of the C-terminal FBXO31 β-barrel. Biophysical and functional studies demonstrate that SCFFBXO31 is capable of recruiting and ubiquitinating cyclin D1 in a phosphorylation-independent manner. Our findings provide a conceptual framework for understanding the substrate specificity of the F-box protein FBXO31 and the mechanism of FBXO31-regulated cyclin D1 protein turnover.

    更新日期:2018-01-10
  • High-resolution structure of podovirus tail adaptor suggests repositioning of an octad motif that mediates the sequential tail assembly
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Lingfei Liang, Haiyan Zhao, Bowen An, Liang Tang

    The sophisticated tail structures of DNA bacteriophages play essential roles in life cycles. Podoviruses P22 and Sf6 have short tails consisting of multiple proteins, among which is a tail adaptor protein that connects the portal protein to the other tail proteins. Assembly of the tail has been shown to occur in a sequential manner to ensure proper molecular interactions, but the underlying mechanism remains to be understood. Here, we report the high-resolution structure of the tail adaptor protein gp7 from phage Sf6. The structure exhibits distinct distribution of opposite charges on two sides of the molecule. A gp7 dodecameric ring model shows an entirely negatively charged surface, suggesting that the assembly of the dodecamer occurs through head-to-tail interactions of the bipolar monomers. The N-terminal helix-loop structure undergoes rearrangement compared with that of the P22 homolog complexed with the portal, which is achieved by repositioning of two consecutive repeats of a conserved octad sequence motif. We propose that the conformation of the N-terminal helix-loop observed in the Sf6-gp7 and P22 portal:gp4 complex represents the pre- and postassembly state, respectively. Such motif repositioning may serve as a conformational switch that creates the docking site for the tail nozzle only after the assembly of adaptor protein to the portal. In addition, the C-terminal portion of gp7 shows conformational flexibility, indicating an induced fit on binding to the portal. These results provide insight into the mechanistic role of the adaptor protein in mediating the sequential assembly of the phage tail.

    更新日期:2018-01-10
  • Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Colin H. Lipper, Ola Karmi, Yang Sung Sohn, Merav Darash-Yahana, Heiko Lammert, Luhua Song, Amy Liu, Ron Mittler, Rachel Nechushtai, José N. Onuchic, Patricia A. Jennings

    The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1–3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased accumulation of mitochondrial labile iron, as well as increased mitochondrial reactive oxygen production. Taken together, our study suggests that the MiNT protein functions in the same pathway as its homodimeric counterparts (mitoNEET and NAF-1), and could be a key player in this pathway within the mitochondria. As such, it represents a target for anticancer or antidiabetic drug development.

    更新日期:2018-01-10
  • LAMOST telescope reveals that Neptunian cousins of hot Jupiters are mostly single offspring of stars that are rich in heavy elements
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Subo Dong, Ji-Wei Xie, Ji-Lin Zhou, Zheng Zheng, Ali Luo

    We discover a population of short-period, Neptune-size planets sharing key similarities with hot Jupiters: both populations are preferentially hosted by metal-rich stars, and both are preferentially found in Kepler systems with single-transiting planets. We use accurate Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) Data Release 4 (DR4) stellar parameters for main-sequence stars to study the distributions of short-period (1d<P<10d)(1d2RRp6R2R⊕≲Rp≲6R⊕), dubbed “Hoptunes.” Also like hot Jupiters, Hoptunes occur more frequently in systems with single-transiting planets although the fraction of Hoptunes occurring in multiples is larger than that of hot Jupiters. About 1%1% of solar-type stars host Hoptunes, and the frequencies of Hoptunes and hot Jupiters increase with consistent trends as a function of [Fe/H]. In the planet radius distribution, hot Jupiters and Hoptunes are separated by a “valley” at approximately Saturn size (in the range of 6RRp10R6R⊕≲Rp≲10R⊕), and this “hot-Saturn valley” represents approximately an order-of-magnitude decrease in planet frequency compared with hot Jupiters and Hoptunes. The empirical “kinship” between Hoptunes and hot Jupiters suggests likely common processes (migration and/or formation) responsible for their existence.

    更新日期:2018-01-10
  • Atmospheric escape from the TRAPPIST-1 planets and implications for habitability
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Chuanfei Dong, Meng Jin, Manasvi Lingam, Vladimir S. Airapetian, Yingjuan Ma, Bart van der Holst

    The presence of an atmosphere over sufficiently long timescales is widely perceived as one of the most prominent criteria associated with planetary surface habitability. We address the crucial question of whether the seven Earth-sized planets transiting the recently discovered ultracool dwarf star TRAPPIST-1 are capable of retaining their atmospheres. To this effect, we carry out numerical simulations to characterize the stellar wind of TRAPPIST-1 and the atmospheric ion escape rates for all of the seven planets. We also estimate the escape rates analytically and demonstrate that they are in good agreement with the numerical results. We conclude that the outer planets of the TRAPPIST-1 system are capable of retaining their atmospheres over billion-year timescales. The consequences arising from our results are also explored in the context of abiogenesis, biodiversity, and searches for future exoplanets. In light of the many unknowns and assumptions involved, we recommend that these conclusions must be interpreted with due caution.

    更新日期:2018-01-10
  • Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Yun Zhang, Yongzhi Qiu, Aaron T. Blanchard, Yuan Chang, Josh M. Brockman, Victor Pui-Yan Ma, Wilbur A. Lam, Khalid Salaita

    Platelet aggregation at the site of vascular injury is essential in clotting. During this process, platelets are bridged by soluble fibrinogen that binds surface integrin receptors. One mystery in the mechanism of platelet aggregation pertains to how resting platelets ignore soluble fibrinogen, the third most abundant protein in the bloodstream, and yet avidly bind immobile fibrinogen on the surface of other platelets at the primary injury site. We speculate that platelet integrins are mechanosensors that test their ligands across the platelet–platelet synapse. To investigate this model, we interrogate human platelets using approaches that include the supported lipid bilayer platform as well as DNA tension sensor technologies. Experiments suggest that platelet integrins require lateral forces to mediate platelet–platelet interactions. Mechanically labile ligands dampen platelet activation, and the onset of piconewton integrin tension coincides with calcium flux. Activated platelets display immobilized fibrinogen on their surface, thus mediating further recruitment of resting platelets. The distribution of integrin tension was shown to be spatially regulated through two myosin-signaling pathways, myosin light chain kinase and Rho-associated kinase. Finally, we discovered that the termination of integrin tension is coupled with the exposure of phosphatidylserine. Our work reveals the highest spatial and temporal resolution maps of platelet integrin mechanics and its role in platelet aggregation, suggesting that platelets are physical substrates for one another that establish mechanical feedback loops of activation. The results are reminiscent of mechanical regulation of the T-cell receptor, E-cadherin, and Notch pathways, suggesting a common feature for signaling at cell junctions.

    更新日期:2018-01-10
  • A mixed-scale dense convolutional neural network for image analysis
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Daniël M. Pelt, James A. Sethian

    Deep convolutional neural networks have been successfully applied to many image-processing problems in recent works. Popular network architectures often add additional operations and connections to the standard architecture to enable training deeper networks. To achieve accurate results in practice, a large number of trainable parameters are often required. Here, we introduce a network architecture based on using dilated convolutions to capture features at different image scales and densely connecting all feature maps with each other. The resulting architecture is able to achieve accurate results with relatively few parameters and consists of a single set of operations, making it easier to implement, train, and apply in practice, and automatically adapts to different problems. We compare results of the proposed network architecture with popular existing architectures for several segmentation problems, showing that the proposed architecture is able to achieve accurate results with fewer parameters, with a reduced risk of overfitting the training data.

    更新日期:2018-01-10
  • Inner Workings: Fishing for artifacts beneath the waves
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Traci Watson

    Fisherman Mike Anderson has accidentally hauled up all manner of oddities in his fishing gear—bits of pottery, lumps of coal, even a silver spoon. But he’d never seen anything like the heavy, jagged block pulled up by his scallop dredge as he cruised near the New England coast in the spring of 2013.

    更新日期:2018-01-10
  • Inactivation of porcine interleukin-1β results in failure of rapid conceptus elongation
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Jeffrey J. Whyte, Ashley E. Meyer, Lee D. Spate, Joshua A. Benne, Raissa Cecil, Melissa S. Samuel, Clifton N. Murphy, Randall S. Prather, Rodney D. Geisert

    Conceptus expansion throughout the uterus of mammalian species with a noninvasive epitheliochorial type of placentation is critical establishing an adequate uterine surface area for nutrient support during gestation. Pig conceptuses undergo a unique rapid morphological transformation to elongate into filamentous threads within 1 h, which provides the uterine surface to support development and maintain functional corpora lutea through the production of estrogen. Conceptus production of a unique interleukin 1β, IL1B2, temporally increases during the period of trophoblast remodeling during elongation. CRISPR/Cas9 gene editing was used to knock out pig conceptus IL1B2 expression and the secretion of IL1B2 during the time of conceptus elongation. Trophoblast elongation occurred on day 14 in wild-type (IL1B2+/+) conceptuses but did not occur in ILB2-null (IL1B2−/−) conceptuses. Although the morphological transition of IL1B2−/− conceptuses was inhibited, expression of a number of conceptus developmental genes was not altered. However, conceptus aromatase expression and estrogen secretion were decreased, indicating that IL1B2 may be involved in the spatiotemporal increase in conceptus estrogen synthesis needed for the establishment of pregnancy in the pig and may serve to regulate the proinflammatory response of endometrium to IL1B2 during conceptus elongation and attachment to the uterine surface.

    更新日期:2018-01-10
  • Two types of aggression in human evolution
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Richard W. Wrangham

    Two major types of aggression, proactive and reactive, are associated with contrasting expression, eliciting factors, neural pathways, development, and function. The distinction is useful for understanding the nature and evolution of human aggression. Compared with many primates, humans have a high propensity for proactive aggression, a trait shared with chimpanzees but not bonobos. By contrast, humans have a low propensity for reactive aggression compared with chimpanzees, and in this respect humans are more bonobo-like. The bimodal classification of human aggression helps solve two important puzzles. First, a long-standing debate about the significance of aggression in human nature is misconceived, because both positions are partly correct. The Hobbes–Huxley position rightly recognizes the high potential for proactive violence, while the Rousseau–Kropotkin position correctly notes the low frequency of reactive aggression. Second, the occurrence of two major types of human aggression solves the execution paradox, concerned with the hypothesized effects of capital punishment on self-domestication in the Pleistocene. The puzzle is that the propensity for aggressive behavior was supposedly reduced as a result of being selected against by capital punishment, but capital punishment is itself an aggressive behavior. Since the aggression used by executioners is proactive, the execution paradox is solved to the extent that the aggressive behavior of which victims were accused was frequently reactive, as has been reported. Both types of killing are important in humans, although proactive killing appears to be typically more frequent in war. The biology of proactive aggression is less well known and merits increased attention.

    更新日期:2018-01-10
  • ZmCCT9 enhances maize adaptation to higher latitudes
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Cheng Huang, Huayue Sun, Dingyi Xu, Qiuyue Chen, Yameng Liang, Xufeng Wang, Guanghui Xu, Jinge Tian, Chenglong Wang, Dan Li, Lishuan Wu, Xiaohong Yang, Weiwei Jin, John F. Doebley, Feng Tian

    From its tropical origin in southwestern Mexico, maize spread over a wide latitudinal cline in the Americas. This feat defies the rule that crops are inhibited from spreading easily across latitudes. How the widespread latitudinal adaptation of maize was accomplished is largely unknown. Through positional cloning and association mapping, we resolved a flowering-time quantitative trait locus to a Harbinger-like transposable element positioned 57 kb upstream of a CCT transcription factor (ZmCCT9). The Harbinger-like element acts in cis to repress ZmCCT9 expression to promote flowering under long days. Knockout of ZmCCT9 by CRISPR/Cas9 causes early flowering under long days. ZmCCT9 is diurnally regulated and negatively regulates the expression of the florigen ZCN8, thereby resulting in late flowering under long days. Population genetics analyses revealed that the Harbinger-like transposon insertion at ZmCCT9 and the CACTA-like transposon insertion at another CCT paralog, ZmCCT10, arose sequentially following domestication and were targeted by selection for maize adaptation to higher latitudes. Our findings help explain how the dynamic maize genome with abundant transposon activity enabled maize to adapt over 90° of latitude during the pre-Columbian era.

    更新日期:2018-01-10
  • ALKBH5-dependent m6A demethylation controls splicing and stability of long 3′-UTR mRNAs in male germ cells
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Chong Tang, Rachel Klukovich, Hongying Peng, Zhuqing Wang, Tian Yu, Ying Zhang, Huili Zheng, Arne Klungland, Wei Yan

    N6-methyladenosine (m6A) represents one of the most common RNA modifications in eukaryotes. Specific m6A writer, eraser, and reader proteins have been identified. As an m6A eraser, ALKBH5 specifically removes m6A from target mRNAs and inactivation of Alkbh5 leads to male infertility in mice. However, the underlying molecular mechanism remains unknown. Here, we report that ALKBH5-mediated m6A erasure in the nuclei of spermatocytes and round spermatids is essential for correct splicing and the production of longer 3′-UTR mRNAs, and failure to do so leads to aberrant splicing and production of shorter transcripts with elevated levels of m6A that are rapidly degraded. Our study identified reversible m6A modification as a critical mechanism of posttranscriptional control of mRNA fate in late meiotic and haploid spermatogenic cells.

    更新日期:2018-01-10
  • Heat activation is intrinsic to the pore domain of TRPV1
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Feng Zhang, Andres Jara-Oseguera, Tsg-Hui Chang, Chanhyung Bae, Sonya M. Hanson, Kenton J. Swartz

    The TRPV1 channel is a sensitive detector of pain-producing stimuli, including noxious heat, acid, inflammatory mediators, and vanilloid compounds. Although binding sites for some activators have been identified, the location of the temperature sensor remains elusive. Using available structures of TRPV1 and voltage-activated potassium channels, we engineered chimeras wherein transmembrane regions of TRPV1 were transplanted into the Shaker Kv channel. Here we show that transplanting the pore domain of TRPV1 into Shaker gives rise to functional channels that can be activated by a TRPV1-selective tarantula toxin that binds to the outer pore of the channel. This pore-domain chimera is permeable to Na+, K+, and Ca2+ ions, and remarkably, is also robustly activated by noxious heat. Our results demonstrate that the pore of TRPV1 is a transportable domain that contains the structural elements sufficient for activation by noxious heat.

    更新日期:2018-01-10
  • Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Akiko Wagatsuma, Teruhiro Okuyama, Chen Sun, Lillian M. Smith, Kuniya Abe, Susumu Tonegawa

    The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the single-trial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus.

    更新日期:2018-01-10
  • Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Noriko Itoh, Yuichiro Itoh, Alessia Tassoni, Emily Ren, Max Kaito, Ai Ohno, Yan Ao, Vista Farkhondeh, Hadley Johnsonbaugh, Josh Burda, Michael V. Sofroniew, Rhonda R. Voskuhl

    Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.

    更新日期:2018-01-10
  • ATM and ATR play complementary roles in the behavior of excitatory and inhibitory vesicle populations
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Aifang Cheng, Teng Zhao, Kai-Hei Tse, Hei-Man Chow, Yong Cui, Liwen Jiang, Shengwang Du, Michael M. T. Loy, Karl Herrup

    ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) are large PI3 kinases whose human mutations result in complex syndromes that include a compromised DNA damage response (DDR) and prominent nervous system phenotypes. Both proteins are nuclear-localized in keeping with their DDR functions, yet both are also found in cytoplasm, including on neuronal synaptic vesicles. In ATM- or ATR-deficient neurons, spontaneous vesicle release is reduced, but a drop in ATM or ATR level also slows FM4-64 dye uptake. In keeping with this, both proteins bind to AP-2 complex components as well as to clathrin, suggesting roles in endocytosis and vesicle recycling. The two proteins play complementary roles in the DDR; ATM is engaged in the repair of double-strand breaks, while ATR deals mainly with single-strand damage. Unexpectedly, this complementarity extends to these proteins’ synaptic function as well. Superresolution microscopy and coimmunoprecipitation reveal that ATM associates exclusively with excitatory (VGLUT1+) vesicles, while ATR associates only with inhibitory (VGAT+) vesicles. The levels of ATM and ATR respond to each other; when ATM is deficient, ATR levels rise, and vice versa. Finally, blocking NMDA, but not GABA, receptors causes ATM levels to rise while ATR levels respond to GABA, but not NMDA, receptor blockade. Taken together, our data suggest that ATM and ATR are part of the cellular “infrastructure” that maintains the excitatory/inhibitory balance of the nervous system. This idea has important implications for the human diseases resulting from their genetic deficiency.

    更新日期:2018-01-10
  • Colorectal cancer specific conditions promote Streptococcus gallolyticus gut colonization
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Laetitia Aymeric, Françoise Donnadieu, Céline Mulet, Laurence du Merle, Giulia Nigro, Azadeh Saffarian, Marion Bérard, Claire Poyart, Sylvie Robine, Béatrice Regnault, Patrick Trieu-Cuot, Philippe J. Sansonetti, Shaynoor Dramsi

    Colonization by Streptococcus gallolyticus subsp. gallolyticus (SGG) is strongly associated with the occurrence of colorectal cancer (CRC). However, the factors leading to its successful colonization are unknown, and whether SGG influences the oncogenic process or benefits from the tumor-prone environment to prevail remains an open question. Here, we elucidate crucial steps that explain how CRC favors SGG colonization. By using mice genetically prone to CRC, we show that SGG colonization is 1,000-fold higher in tumor-bearing mice than in normal mice. This selective advantage occurs at the expense of resident intestinal enterococci. An SGG-specific locus encoding a bacteriocin (“gallocin”) is shown to kill enterococci in vitro. Importantly, bile acids strongly enhance this bacteriocin activity in vivo, leading to greater SGG colonization. Constitutive activation of the Wnt pathway, one of the earliest signaling alterations in CRC, and the decreased expression of the bile acid apical transporter gene Slc10A2, as an effect of the Apc founding mutation, may thereby sustain intestinal colonization by SGG. We conclude that CRC-specific conditions promote SGG colonization of the gut by replacing commensal enterococci in their niche.

    更新日期:2018-01-10
  • Stand-alone ClpG disaggregase confers superior heat tolerance to bacteria
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Changhan Lee, Kamila B. Franke, Shady Mansour Kamal, Hyunhee Kim, Heinrich Lünsdorf, Jasmin Jäger, Manfred Nimtz, Janja Trček, Lothar Jänsch, Bernd Bukau, Axel Mogk, Ute Römling

    AAA+ disaggregases solubilize aggregated proteins and confer heat tolerance to cells. Their disaggregation activities crucially depend on partner proteins, which target the AAA+ disaggregases to protein aggregates while concurrently stimulating their ATPase activities. Here, we report on two potent ClpG disaggregase homologs acquired through horizontal gene transfer by the species Pseudomonas aeruginosa and subsequently abundant P. aeruginosa clone C. ClpG exhibits high, stand-alone disaggregation potential without involving any partner cooperation. Specific molecular features, including high basal ATPase activity, a unique aggregate binding domain, and almost exclusive expression in stationary phase distinguish ClpG from other AAA+ disaggregases. Consequently, ClpG largely contributes to heat tolerance of P. aeruginosa primarily in stationary phase and boosts heat resistance 100-fold when expressed in Escherichia coli. This qualifies ClpG as a potential persistence and virulence factor in P. aeruginosa.

    更新日期:2018-01-10
  • Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Duo An, Alan Chiu, James A. Flanders, Wei Song, Dahua Shou, Yen-Chun Lu, Lars G. Grunnet, Louise Winkel, Camilla Ingvorsen, Nicolaj Strøyer Christophersen, Johannes Josef Fels, Fredrik Wolfhagen Sand, Yewei Ji, Ling Qi, Yehudah Pardo, Dan Luo, Meredith Silberstein, Jintu Fan, Minglin Ma

    Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement. Here, we report a simple cell encapsulation design that is readily scalable and conveniently retrievable. The key to this design was to engineer a highly wettable, Ca2+-releasing nanoporous polymer thread that promoted uniform in situ cross-linking and strong adhesion of a thin layer of alginate hydrogel around the thread. The device provided immunoprotection of rat islets in immunocompetent C57BL/6 mice in a short-term (1-mo) study, similar to neat alginate fibers. However, the mechanical property of the device, critical for handling and retrieval, was much more robust than the neat alginate fibers due to the reinforcement of the central thread. It also had facile mass transfer due to the short diffusion distance. We demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 mo as well as in immunodeficient SCID-Beige mice using human islets for 4 mo. We further showed, as a proof of concept, the scalability and retrievability in dogs. After 1 mo of implantation in dogs, the device could be rapidly retrieved through a minimally invasive laparoscopic procedure. This encapsulation device may contribute to a cellular therapy for T1D because of its retrievability and scale-up potential.

    更新日期:2018-01-10
  • FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Ho-Keun Kwon, Hui-Min Chen, Diane Mathis, Christophe Benoist

    FoxP3+ regulatory T cells (Tregs) are a central element of immunological tolerance. FoxP3 is the key determining transcription factor of the Treg lineage, interacting with numerous cofactors and transcriptional targets to determine the many facets of Treg function. Its absence leads to devastating lymphoproliferation and autoimmunity in scurfy mutant mice and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients. To finely map transcriptionally active regions of the protein, with respect to disease-causing variation, we performed a systematic alanine-scan mutagenesis of FoxP3, assessing mutational impacts on DNA binding and transcriptional activation or repression. The mutations affected transcriptional activation and repression in a variegated manner involving multiple regions of the protein and varying between different transcriptional targets of FoxP3. There appeared to be different modalities for target genes related to classic immunosuppressive function vs. those related to atypical or tissue-Treg functions. Relevance to in vivo Treg biology was established by introducing some of the subtle Foxp3 mutations into the mouse germline by CRISPR-based genome editing. The resulting mice showed Treg populations in normal numbers and exhibited no overt autoimmune manifestations. However, Treg functional defects were revealed upon competition or by system stress, manifest as a strikingly heightened susceptibility to provoked colitis, and conversely by greater resistance to tumors. These observations suggest that some of the missense mutations that segregate in human populations, but do not induce IPEX manifestations, may have unappreciated consequences in other diseases.

    更新日期:2018-01-10
  • Histone demethylase LSD1 regulates hematopoietic stem cells homeostasis and protects from death by endotoxic shock
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Jianxun Wang, Kaoru Saijo, Dylan Skola, Chunyu Jin, Qi Ma, Daria Merkurjev, Christopher K. Glass, Michael G. Rosenfeld

    Hematopoietic stem cells (HSCs) maintain a quiescent state during homeostasis, but with acute infection, they exit the quiescent state to increase the output of immune cells, the so-called “emergency hematopoiesis.” However, HSCs’ response to severe infection during septic shock and the pathological impact remain poorly elucidated. Here, we report that the histone demethylase KDM1A/LSD1, serving as a critical regulator of mammalian hematopoiesis, is a negative regulator of the response to inflammation in HSCs during endotoxic shock typically observed during acute bacterial or viral infection. Inflammation-induced LSD1 deficiency results in an acute expansion of a pathological population of hyperproliferative and hyperinflammatory myeloid progenitors, resulting in a septic shock phenotype and acute death. Unexpectedly, in vivo administration of bacterial lipopolysaccharide (LPS) to wild-type mice results in acute suppression of LSD1 in HSCs with a septic shock phenotype that resembles that observed following induced deletion of LSD1. The suppression of LSD1 in HSCs is caused, at least in large part, by a cohort of inflammation-induced microRNAs. Significantly, reconstitution of mice with bone marrow progenitor cells expressing inhibitors of these inflammation-induced microRNAs blocked the suppression of LSD1 in vivo following acute LPS administration and prevented mortality from endotoxic shock. Our results indicate that LSD1 activators or miRNA antagonists could serve as a therapeutic approach for life-threatening septic shock characterized by dysfunction of HSCs.

    更新日期:2018-01-10
  • Ancient polymorphisms and divergence hitchhiking contribute to genomic islands of divergence within a poplar species complex
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Tao Ma, Kun Wang, Quanjun Hu, Zhenxiang Xi, Dongshi Wan, Qian Wang, Jianju Feng, Dechun Jiang, Hamid Ahani, Richard J. Abbott, Martin Lascoux, Eviatar Nevo, Jianquan Liu

    How genome divergence eventually leads to speciation is a topic of prime evolutionary interest. Genomic islands of elevated divergence are frequently reported between diverging lineages, and their size is expected to increase with time and gene flow under the speciation-with-gene-flow model. However, such islands can also result from divergent sorting of ancient polymorphisms, recent ecological selection regardless of gene flow, and/or recurrent background selection and selective sweeps in low-recombination regions. It is challenging to disentangle these nonexclusive alternatives, but here we attempt to do this in an analysis of what drove genomic divergence between four lineages comprising a species complex of desert poplar trees. Within this complex we found that two morphologically delimited species, Populus euphratica and Populus pruinosa, were paraphyletic while the four lineages exhibited contrasting levels of gene flow and divergence times, providing a good system for testing hypotheses on the origin of divergence islands. We show that the size and number of genomic islands that distinguish lineages are not associated with either rate of recent gene flow or time of divergence. Instead, they are most likely derived from divergent sorting of ancient polymorphisms and divergence hitchhiking. We found that highly diverged genes under lineage-specific selection and putatively involved in ecological and morphological divergence occur both within and outside these islands. Our results highlight the need to incorporate demography, absolute divergence measurement, and gene flow rate to explain the formation of genomic islands and to identify potential genomic regions involved in speciation.

    更新日期:2018-01-10
  • Multiple origins of interdependent endosymbiotic complexes in a genus of cicadas
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Piotr Łukasik, Katherine Nazario, James T. Van Leuven, Matthew A. Campbell, Mariah Meyer, Anna Michalik, Pablo Pessacq, Chris Simon, Claudio Veloso, John P. McCutcheon

    Bacterial endosymbionts that provide nutrients to hosts often have genomes that are extremely stable in structure and gene content. In contrast, the genome of the endosymbiont Hodgkinia cicadicola has fractured into multiple distinct lineages in some species of the cicada genus Tettigades. To better understand the frequency, timing, and outcomes of Hodgkinia lineage splitting throughout this cicada genus, we sampled cicadas over three field seasons in Chile and performed genomics and microscopy on representative samples. We found that a single ancestral Hodgkinia lineage has split at least six independent times in Tettigades over the last 4 million years, resulting in complexes of between two and six distinct Hodgkinia lineages per host. Individual genomes in these symbiotic complexes differ dramatically in relative abundance, genome size, organization, and gene content. Each Hodgkinia lineage retains a small set of core genes involved in genetic information processing, but the high level of gene loss experienced by all genomes suggests that extensive sharing of gene products among symbiont cells must occur. In total, Hodgkinia complexes that consist of multiple lineages encode nearly complete sets of genes present on the ancestral single lineage and presumably perform the same functions as symbionts that have not undergone splitting. However, differences in the timing of the splits, along with dissimilar gene loss patterns on the resulting genomes, have led to very different outcomes of lineage splitting in extant cicadas.

    更新日期:2018-01-10
  • Hybrid speciation leads to novel male secondary sexual ornamentation of an Amazonian bird
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Alfredo O. Barrera-Guzmán, Alexandre Aleixo, Matthew D. Shawkey, Jason T. Weir

    Hybrid speciation is rare in vertebrates, and reproductive isolation arising from hybridization is infrequently demonstrated. Here, we present evidence supporting a hybrid-speciation event involving the genetic admixture of the snow-capped (Lepidothrix nattereri) and opal-crowned (Lepidothrix iris) manakins of the Amazon basin, leading to the formation of the hybrid species, the golden-crowned manakin (Lepidothrix vilasboasi). We used a genome-wide SNP dataset together with analysis of admixture, population structure, and coalescent modeling to demonstrate that the golden-crowned manakin is genetically an admixture of these species and does not represent a hybrid zone but instead formed through ancient genetic admixture. We used spectrophotometry to quantify the coloration of the species-specific male crown patches. Crown patches are highly reflective white (snow-capped manakin) or iridescent whitish-blue to pink (opal-crowned manakin) in parental species but are a much less reflective yellow in the hybrid species. The brilliant coloration of the parental species results from nanostructural organization of the keratin matrix feather barbs of the crown. However, using electron microscopy, we demonstrate that the structural organization of this matrix is different in the two parental species and that the hybrid species is intermediate. The intermediate nature of the crown barbs, resulting from past admixture appears to have rendered a duller structural coloration. To compensate for reduced brightness, selection apparently resulted in extensive thickening of the carotenoid-laden barb cortex, producing the yellow crown coloration. The evolution of this unique crown-color signal likely culminated in premating isolation of the hybrid species from both parental species.

    更新日期:2018-01-10
  • Listeria monocytogenes triggers noncanonical autophagy upon phagocytosis, but avoids subsequent growth-restricting xenophagy
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Gabriel Mitchell, Mandy I. Cheng, Chen Chen, Brittney N. Nguyen, Aaron T. Whiteley, Sara Kianian, Jeffery S. Cox, Douglas R. Green, Kent L. McDonald, Daniel A. Portnoy

    Xenophagy is a selective macroautophagic process that protects the host cytosol by entrapping and delivering microbes to a degradative compartment. Both noncanonical autophagic pathways and xenophagy are activated by microbes during infection, but the relative importance and function of these distinct processes are not clear. In this study, we used bacterial and host mutants to dissect the contribution of autophagic processes responsible for bacterial growth restriction of Listeria monocytogenes. L. monocytogenes is a facultative intracellular pathogen that escapes from phagosomes, grows in the host cytosol, and avoids autophagy by expressing three determinants of pathogenesis: two secreted phospholipases C (PLCs; PlcA and PlcB) and a surface protein (ActA). We found that shortly after phagocytosis, wild-type (WT) L. monocytogenes escaped from a noncanonical autophagic process that targets damaged vacuoles. During this process, the autophagy marker LC3 localized to single-membrane phagosomes independently of the ULK complex, which is required for initiation of macroautophagy. However, growth restriction of bacteria lacking PlcA, PlcB, and ActA required FIP200 and TBK1, both involved in the engulfment of microbes by xenophagy. Time-lapse video microscopy revealed that deposition of LC3 on L. monocytogenes-containing vacuoles via noncanonical autophagy had no apparent role in restricting bacterial growth and that, upon access to the host cytosol, WT L. monocytogenes utilized PLCs and ActA to avoid subsequent xenophagy. In conclusion, although noncanonical autophagy targets phagosomes, xenophagy was required to restrict the growth of L. monocytogenes, an intracellular pathogen that damages the entry vacuole.

    更新日期:2018-01-10
  • Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Wan-Jin Lu, Randall K. Mann, Allison Nguyen, Tingting Bi, Max Silverstein, Jean Y. Tang, Xiaoke Chen, Philip A. Beachy

    How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

    更新日期:2018-01-10
  • RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases
    PNAS (IF 9.661) Pub Date : 2018-01-09
    Geng-Xian Shi, Won Seok Yang, Ling Jin, Michelle L. Matter, Joe W. Ramos

    Directed migration is essential for cell motility in many processes, including development and cancer cell invasion. RSKs (p90 ribosomal S6 kinases) have emerged as central regulators of cell migration; however, the mechanisms mediating RSK-dependent motility remain incompletely understood. We have identified a unique signaling mechanism by which RSK2 promotes cell motility through leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. RSK2 directly interacts with LARG and nucleotide-bound Rho isoforms, but not Rac1 or Cdc42. We further show that epidermal growth factor or FBS stimulation induces association of endogenous RSK2 with LARG and LARG with RhoA. In response to these stimuli, RSK2 phosphorylates LARG at Ser1288 and thereby activates RhoA. Phosphorylation of RSK2 at threonine 577 is essential for activation of LARG-RhoA. Moreover, RSK2-mediated motility signaling depends on RhoA and -B, but not RhoC. These results establish a unique RSK2-dependent LARG-RhoA signaling module as a central organizer of directed cell migration and invasion.

    更新日期:2018-01-10
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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