• Assessment of genetic factor and depression interactions for asthma symptom severity in cohorts of childhood and elderly asthmatics

      Park, Heung-Woo; Song, Woo-Jung; Cho, Sang-Heon; McGeachie, Michael J.; Martinez, Fernando; Mauger, Dave; Bender, Bruce G.; Tantisira, Kelan G.; Univ Arizona, Arizona Resp Ctr (NATURE PUBLISHING GROUP, 2018-07-04)
      It is well known that depression is associated with asthma symptoms. We assessed the combined effects of genetic factors and depression on asthma symptom severity using Bayesian network (BN) analysis. The common 100 top-ranked single-nucleotide polymorphisms (SNPs) were obtained from two genome-wide association studies of symptom severity in two childhood asthmatics trials (CAMP (Childhood Asthma Management Program) and CARE (Childhood Asthma Research and Education)). Using SNPs plus five discretized variables (depression, anxiety, age, sex, and race), we performed BN analysis in 529 CAMP subjects. We identified two nodes (depression and rs4672619 mapping to ERBB4 (Erb-B2 receptor tyrosine kinase 4)) that were within the Markov neighborhood of the symptom node in the network and then evaluated the interactive effects of depressive status and rs4672619 genotypes on asthma symptom severity. In childhood asthmatics with homozygous reference alleles, severe depression was related to less severe symptoms. However, in childhood asthmatics with heterozygous alleles and homozygous variant alleles, depression and symptom severity showed a positive correlation (interaction permutation P value =0.019). We then tried to evaluate whether the interactive effects that we found were sustained in another independent cohort of elderly asthmatics. Contrary to the findings from childhood asthmatics, elderly asthmatics with homozygous reference alleles showed a positive correlation between depression and symptom severity, and elderly asthmatics with heterozygous alleles and homozygous variant alleles showed a negative correlation (interaction permutation P value =0.003). In conclusion, we have identified a novel SNP, rs4672619, that shows interactive effects with depression on asthma symptom severity in childhood and elderly asthmatics in opposite directions.
    • Association of UCP1, UCP2 and UCP3 gene polymorphisms with cardiovascular disease risk factors in European adolescents: the HELENA study

      Pascual-Gamarra, Jose M; Salazar-Tortosa, Diego F; Labayen, Idoia; Rupérez, Azahara I; Leclercq, Catherine; Marcos, Ascension; Gómez, Sonia; Moreno, Luis A; Meirhaeghe, Aline; Castillo, Manuel J; et al. (NATURE PUBLISHING GROUP, 2020-01-03)
      Background Cardiovascular diseases (CVDs) are responsible for 31% of all deaths worldwide. Genetic predisposition to CVDs in adolescents remains largely unknown. The aim of this study was to examine the association of UCP1, UCP2 and UCP3 gene polymorphisms with CVD risk factors in European adolescents. Method A cross-sectional study that involves 1.057 European adolescents (12-18 years old) from the HELENA study. A total of 18 polymorphisms of UCP1, UCP2 and UCP3 genes were genotyped. We measured serum total cholesterol, high-density lipoprotein,low-density lipoprotein, ApoA1, ApoB, leptin, triglycerides, glucose, insulin and blood pressure, and calculated HOMA (homeostatic model assessment), Quantitative Insulin Sensitivity Check Index (QUICKI) and a CVD risk score. Results The G allele of UCP2 rs2735572 and T allele of UCP2 rs17132534 were associated with higher diastolic blood pressure (P = 0.001; false discovery rate [FDR] = 0.009 and P = 8e-04; FDR = 0.009, respectively). We observed that the AATAG haplotype of UCP1 was associated with higher serum ApoB/ApoA1 (P = 0.008; FDR = 0.031) and ApoB levels (P = 0.008; FDR = 0.031). Moreover, the ACC haplotype of UCP3 was associated with a higher CVD risk score (P = 0.0036; FDR = 0.01). Conclusions Two UCP2 polymorphisms and haplotypes of UCP1 and UCP3 were associated with CVD risk factors. These findings suggest that UCPs may have a role in the development of CVD already in adolescents.
    • Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

      Daya, Michelle; Rafaels, Nicholas; Brunetti, Tonya M; Chavan, Sameer; Levin, Albert M; Shetty, Aniket; Gignoux, Christopher R; Boorgula, Meher Preethi; Wojcik, Genevieve; Campbell, Monica; et al. (NATURE PUBLISHING GROUP, 2019-02-20)
      Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.
    • Atmospheric deposition, CO2, and change in the land carbon sink

      Fernández-Martínez, M.; Vicca, S.; Janssens, I. A.; Ciais, P.; Obersteiner, M.; Bartrons, M.; Sardans, J.; Verger, A.; Canadell, J. G.; Chevallier, F.; et al. (NATURE PUBLISHING GROUP, 2017-08-29)
      Concentrations of atmospheric carbon dioxide (CO2) have continued to increase whereas atmospheric deposition of sulphur and nitrogen has declined in Europe and the USA during recent decades. Using time series of flux observations from 23 forests distributed throughout Europe and the USA, and generalised mixed models, we found that forest-level net ecosystem production and gross primary production have increased by 1% annually from 1995 to 2011. Statistical models indicated that increasing atmospheric CO2 was the most important factor driving the increasing strength of carbon sinks in these forests. We also found that the reduction of sulphur deposition in Europe and the USA lead to higher recovery in ecosystem respiration than in gross primary production, thus limiting the increase of carbon sequestration. By contrast, trends in climate and nitrogen deposition did not significantly contribute to changing carbon fluxes during the studied period. Our findings support the hypothesis of a general CO2-fertilization effect on vegetation growth and suggest that, so far unknown, sulphur deposition plays a significant role in the carbon balance of forests in industrialized regions. Our results show the need to include the effects of changing atmospheric composition, beyond CO2, to assess future dynamics of carbon-climate feedbacks not currently considered in earth system/climate modelling.
    • The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain

      Peng, Yun; Lu, Zhongming; Li, Guohui; Piechowicz, Mariel; Anderson, Miranda; Uddin, Yasin; Wu, Jie; Qiu, Shengfeng; Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix (NATURE PUBLISHING GROUP, 2016-07)
      The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which plays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization, and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD.
    • A bacterial filter protects and structures the gut microbiome of an insect

      Lanan, Michele Caroline; Pos Rodrigues, Pedro Augusto; Agellon, Al; Jansma, Patricia; Wheeler, Diana Esther; Graduate Interdisciplinary Program in Entomology and Insect Science, University of Arizona; School of Animal and Comparative Biomedical Sciences, University of Arizona; Department of Neuroscience, University of Arizona; Department of Entomology, University of Arizona (NATURE PUBLISHING GROUP, 2016-08)
      Associations with symbionts within the gut lumen of hosts are particularly prone to disruption due to the constant influx of ingested food and non-symbiotic microbes, yet we know little about how partner fidelity is maintained. Here we describe for the first time the existence of a gut morphological filter capable of protecting an animal gut microbiome from disruption. The proventriculus, a valve located between the crop and midgut of insects, functions as a micro-pore filter in the Sonoran Desert turtle ant (Cephalotes rohweri), blocking the entry of bacteria and particles ⩾0.2 μm into the midgut and hindgut while allowing passage of dissolved nutrients. Initial establishment of symbiotic gut bacteria occurs within the first few hours after pupation via oral–rectal trophallaxis, before the proventricular filter develops. Cephalotes ants are remarkable for having maintained a consistent core gut microbiome over evolutionary time and this partner fidelity is likely enabled by the proventricular filtering mechanism. In addition, the structure and function of the cephalotine proventriculus offers a new perspective on organismal resistance to pathogenic microbes, structuring of gut microbial communities, and development and maintenance of host–microbe fidelity both during the animal life cycle and over evolutionary time.
    • A bed nucleus of stria terminalis microcircuit regulating inflammation-associated modulation of feeding

      Wang, Yong; Kim, JungMin; Schmit, Matthew B; Cho, Tiffany S; Fang, Caohui; Cai, Haijiang; Univ Arizona, Dept Neurosci; Univ Arizona, Grad Interdisciplinary Program Neurosci; Univ Arizona, Bio5 Inst; Univ Arizona, Dept Neurol (NATURE PUBLISHING GROUP, 2019-06-24)
      Loss of appetite or anorexia associated with inflammation impairs quality of life and increases morbidity in many diseases. However, the exact neural mechanism that mediates inflammation-associated anorexia is still poorly understood. Here we identified a population of neurons, marked by the expression of protein kinase C-delta, in the oval region of the bed nucleus of the stria terminalis (BNST), which are activated by various inflammatory signals. Silencing of these neurons attenuates the anorexia caused by these inflammatory signals. Our results demonstrate that these neurons mediate bidirectional control of general feeding behaviors. These neurons inhibit the lateral hypothalamus-projecting neurons in the ventrolateral part of BNST to regulate feeding, receive inputs from the canonical feeding regions of arcuate nucleus and parabrachial nucleus. Our data therefore define a BNST microcircuit that might coordinate canonical feeding centers to regulate food intake, which could offer therapeutic targets for feeding-related diseases such as anorexia and obesity.
    • Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

      Wagner, Matias; Osborn, Daniel P S; Gehweiler, Ina; Nagel, Maike; Ulmer, Ulrike; Bakhtiari, Somayeh; Amouri, Rim; Boostani, Reza; Hentati, Faycal; Hockley, Maryam M; et al. (NATURE PUBLISHING GROUP, 2019-10-21)
      Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.
    • Biodiversity of protists and nematodes in the wild nonhuman primate gut

      Mann, Allison E; Mazel, Florent; Lemay, Matthew A; Morien, Evan; Billy, Vincent; Kowalewski, Martin; Di Fiore, Anthony; Link, Andrés; Goldberg, Tony L; Tecot, Stacey; et al. (NATURE PUBLISHING GROUP, 2019-11-12)
      Documenting the natural diversity of eukaryotic organisms in the nonhuman primate (NHP) gut is important for understanding the evolution of the mammalian gut microbiome, its role in digestion, health and disease, and the consequences of anthropogenic change on primate biology and conservation. Despite the ecological significance of gut-associated eukaryotes, little is known about the factors that influence their assembly and diversity in mammals. In this study, we used an 18S rRNA gene fragment metabarcoding approach to assess the eukaryotic assemblage of 62 individuals representing 16 NHP species. We find that cercopithecoids, and especially the cercopithecines, have substantially higher alpha diversity than other NHP groups. Gut-associated protists and nematodes are widespread among NHPs, consistent with their ancient association with NHP hosts. However, we do not find a consistent signal of phylosymbiosis or host-species specificity. Rather, gut eukaryotes are only weakly structured by primate phylogeny with minimal signal from diet, in contrast to previous reports of NHP gut bacteria. The results of this study indicate that gut-associated eukaryotes offer different information than gut-associated bacteria and add to our understanding of the structure of the gut microbiome.
    • Biotic soil-plant interaction processes explain most of hysteric soil CO2 efflux response to temperature in cross-factorial mesocosm experiment

      Dusza, Yann; Sanchez-Canete, Enrique P.; Le Galliard, Jean-Francois; Ferriere, Regis; Chollet, Simon; Massol, Florent; Hansart, Amandine; Juarez, Sabrina; Dontsova, Katerina; van Haren, Joost; et al. (NATURE PUBLISHING GROUP, 2020-01)
      Ecosystem carbon flux partitioning is strongly influenced by poorly constrained soil CO2 efflux (F-soil). Simple model applications (Arrhenius and Q(10)) do not account for observed diel hysteresis between F-soil and soil temperature. How this hysteresis emerges and how it will respond to variation in vegetation or soil moisture remains unknown. We used an ecosystem-level experimental system to independently control potential abiotic and biotic drivers of the F-soil-T hysteresis. We hypothesized a principally biological cause for the hysteresis. Alternatively, F-soil hysteresis is primarily driven by thermal convection through the soil profile. We conducted experiments under normal, fluctuating diurnal soil temperatures and under conditions where we held soil temperature near constant. We found (i) significant and nearly equal amplitudes of hysteresis regardless of soil temperature regime, and (ii) the amplitude of hysteresis was most closely tied to baseline rates of F-soil, which were mostly driven by photosynthetic rates. Together, these findings suggest a more biologically-driven mechanism associated with photosynthate transport in yielding the observed patterns of soil CO2 efflux being out of sync with soil temperature. These findings should be considered on future partitioning models of ecosystem respiration.
    • Borderline personality disorder

      Gunderson, John G.; Herpertz, Sabine C.; Skodol, Andrew E.; Torgersen, Svenn; Zanarini, Mary C.; Univ Arizona, Coll Med, Dept Psychiat (NATURE PUBLISHING GROUP, 2018-05-24)
      Caretakers are often intimidated or alienated by patients with borderline personality disorder (BPD), compounding the clinical challenges posed by the severe morbidity, high social costs and substantial prevalence of this disorder in many health-care settings. BPD is found in similar to 1.7% of the general population but in 15-28% of patients in psychiatric clinics or hospitals and in a large proportion of individuals seeking help for psychological problems in general health facilities. BPD is characterized by extreme sensitivity to perceived interpersonal slights, an unstable sense of self, intense and volatile emotionality and impulsive behaviours that are often self-destructive. Most patients gradually enter symptomatic remission, and their rate of remission can be accelerated by evidence-based psychosocial treatments. Although self-harming behaviours and proneness to crisis can decrease over time, the natural course and otherwise effective treatments of BPD usually leave many patients with persistent and severe social disabilities related to depression or self-harming behaviours. Thus, clinicians need to actively enquire about the central issues of interpersonal relations and unstable identity. Failure to correctly diagnose patients with BPD leads to misleading pharmacological interventions that rarely succeed. Whether the definition of BPD should change is under debate that is linked to not fully knowing the nature of this disorder.
    • Breast Cancer Cell Invasion into a Three Dimensional Tumor-Stroma Microenvironment

      Truong, Danh; Puleo, Julieann; Llave, Alison; Mouneimne, Ghassan; Kamm, Roger D.; Nikkhah, Mehdi; Univ Arizona, Ctr Canc, Dept Cellular & Mol Med (NATURE PUBLISHING GROUP, 2016-09-28)
      In this study, to model 3D chemotactic tumor-stroma invasion in vitro, we developed an innovative microfluidic chip allowing side-by-side positioning of 3D hydrogel-based matrices. We were able to (1) create a dual matrix architecture that extended in a continuous manner, thus allowing invasion from one 3D matrix to another, and (2) establish distinct regions of tumor and stroma cell/ECM compositions, with a clearly demarcated tumor invasion front, thus allowing us to quantitatively analyze progression of cancer cells into the stroma at a tissue or single-cell level. We showed significantly enhanced cancer cell invasion in response to a transient gradient of epidermal growth factor (EGF). 3D tracking at the single-cell level displayed increased migration speed and persistence. Subsequently, we analyzed changes in expression of EGF receptors, cell aspect ratio, and protrusive activity. These findings show the unique ability of our model to quantitatively analyze 3D chemotactic invasion, both globally by tracking the progression of the invasion front, and at the single-cell level by examining changes in cellular behavior and morphology using high-resolution imaging. Taken together, we have shown a novel model recapitulating 3D tumor-stroma interactions for studies of real-time cell invasion and morphological changes within a single platform.
    • California's methane super-emitters

      Duren, Riley M; Thorpe, Andrew K; Foster, Kelsey T; Rafiq, Talha; Hopkins, Francesca M; Yadav, Vineet; Bue, Brian D; Thompson, David R; Conley, Stephen; Colombi, Nadia K; et al. (NATURE PUBLISHING GROUP, 2019-11-07)
      Methane is a powerful greenhouse gas and is targeted for emissions mitigation by the US state of California and other jurisdictions worldwide1,2. Unique opportunities for mitigation are presented by point-source emitters-surface features or infrastructure components that are typically less than 10 metres in diameter and emit plumes of highly concentrated methane3. However, data on point-source emissions are sparse and typically lack sufficient spatial and temporal resolution to guide their mitigation and to accurately assess their magnitude4. Here we survey more than 272,000 infrastructure elements in California using an airborne imaging spectrometer that can rapidly map methane plumes5-7. We conduct five campaigns over several months from 2016 to 2018, spanning the oil and gas, manure-management and waste-management sectors, resulting in the detection, geolocation and quantification of emissions from 564 strong methane point sources. Our remote sensing approach enables the rapid and repeated assessment of large areas at high spatial resolution for a poorly characterized population of methane emitters that often appear intermittently and stochastically. We estimate net methane point-source emissions in California to be 0.618 teragrams per year (95 per cent confidence interval 0.523-0.725), equivalent to 34-46 per cent of the state's methane inventory8 for 2016. Methane 'super-emitter' activity occurs in every sector surveyed, with 10 per cent of point sources contributing roughly 60 per cent of point-source emissions-consistent with a study of the US Four Corners region that had a different sectoral mix9. The largest methane emitters in California are a subset of landfills, which exhibit persistent anomalous activity. Methane point-source emissions in California are dominated by landfills (41 per cent), followed by dairies (26 per cent) and the oil and gas sector (26 per cent). Our data have enabled the identification of the 0.2 per cent of California's infrastructure that is responsible for these emissions. Sharing these data with collaborating infrastructure operators has led to the mitigation of anomalous methane-emission activity10.
    • Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca2+ oscillations in mouse pancreatic acinar cells

      Huang, Zebing; Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Zhang, Haiying; Xia, Kunkun; Chen, Dejie; et al. (NATURE PUBLISHING GROUP, 2016-07-19)
      Emerging evidence demonstrates that the blockade of intracellular Ca2+ signals may protect pancreatic acinar cells against Ca2+ overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB(2)Rs modulate intracellular Ca2+ signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca2+ oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB(2)Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca2+ oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca2+ oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB(2)Rs eliminates ACh-induced Ca2+ oscillations and L-arginine-induced enhancement of Ca2+ signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis.
    • Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

      Pandey, Ritu; Zhou, Muhan; Islam, Shariful; Chen, Baowei; Barker, Natalie K; Langlais, Paul; Srivastava, Anup; Luo, Moulun; Cooke, Laurence S; Weterings, Eric; et al. (NATURE PUBLISHING GROUP, 2019-12-04)
      We investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6-/- cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.
    • The Cardamine hirsuta genome offers insight into the evolution of morphological diversity

      Gan, Xiangchao; Hay, Angela; Kwantes, Michiel; Haberer, Georg; Hallab, Asis; Ioio, Raffaele Dello; Hofhuis, Hugo; Pieper, Bjorn; Cartolano, Maria; Neumann, Ulla; et al. (NATURE PUBLISHING GROUP, 2016-10-31)
      Finding causal relationships between genotypic and phenotypic variation is a key focus of evolutionary biology, human genetics and plant breeding. To identify genome-wide patterns underlying trait diversity, we assembled a high-quality reference genome of Cardamine hirsuta, a close relative of the model plant Arabidopsis thaliana. We combined comparative genome and transcriptome analyses with the experimental tools available in C. hirsuta to investigate gene function and phenotypic diversification. Our findings highlight the prevalent role of transcription factors and tandem gene duplications in morphological evolution. We identified a specific role for the transcriptional regulators PLETHORA5/7 in shaping leaf diversity and link tandem gene duplication with differential gene expression in the explosive seed pod of C. hirsuta. Our work highlights the value of comparative approaches in genetically tractable species to understand the genetic basis for evolutionary change.
    • A catalogue of somatic NRF2 gain-of-function mutations in cancer

      Kerins, Michael John; Ooi, Aikseng; Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol (NATURE PUBLISHING GROUP, 2018-08-27)
      Identification and characterization of somatic mutations in cancer have important prognostication and treatment implications. Genes encoding the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), are frequently mutated in cancer. These mutations drive constitutive NRF2 activation and correlate with poor prognosis. Despite its apparent significance, a comprehensive catalogue of somatic NRF2 mutations across different tumor types is still lacking. Here, we catalogue NRF2 mutations in The Cancer Genome Atlas (TCGA) database. 226 unique NRF2-mutant tumors were identified from 10,364 cases. NRF2 mutations were found in 21 out of the 33 tumor types. A total of 11 hotspots were identified. Of these, mutation to the R34 position was most frequent. Notably, R34 and D29 mutations were overrepresented in bladder, lung, and uterine cancers. Analyses of corresponding RNA sequencing data using a de novo derived gene expression classifier showed that the R34 mutations drive constitutive NRF2 activation with a selection pressure biased against the formation of R34L. Of all R34 mutants, R34L conferred the least degree of protein stabilization, suggesting a pro-tumor NRF2 half-life threshold. Our findings offer a comprehensive catalogue of NRF2 mutations in cancer that can help prognostication and NRF2 research.
    • Cellular information dynamics through transmembrane flow of ions

      Gatenby, Robert A.; Frieden, B. Roy; Univ Arizona, Coll Opt Sci (NATURE PUBLISHING GROUP, 2017-11-08)
      We propose cells generate large transmembrane ion gradients to form information circuits that detect, process, and respond to environmental perturbations or signals. In this model, the specialized gates of transmembrane ion channels function as information detectors that communicate to the cell through rapid and (usually) local pulses of ions. Information in the ion "puffs" is received and processed by the cell through resulting changes in charge density and/or mobile cation (and/or anion) concentrations alter the localization and function of peripheral membrane proteins. The subsequent changes in protein binding to the membrane or activation of K+, Ca2+ or Mg2+ -dependent enzymes then constitute a cellular response to the perturbation. To test this hypothesis we analyzed ion-based signal transmission as a communication channel operating with coded inputs and decoded outputs. By minimizing the Kullback-Leibler cross entropy H-KL(p||q) between concentrations of the ion species inside p(i)(t) i = 1,.,N , and outside q(i)(t) the cell membrane, we find signal transmission through transmembrane ion flow forms an optimal Shannon information channel that minimizes information loss and maximizes transmission speed. We demonstrate the ion dynamics in neuronal action potentials described by Hodgkin and Huxley (including the equations themselves) represent a special case of these general information principles.
    • A centrosome interactome provides insight into organelle assembly and reveals a non-duplication role for Plk4

      Galletta, Brian J.; Fagerstrom, Carey J.; Schoborg, Todd A.; McLamarrah, Tiffany A.; Ryniawec, John M.; Buster, Daniel W.; Slep, Kevin C.; Rogers, Gregory C.; Rusan, Nasser M.; Univ Arizona, Ctr Canc, Dept Cellular & Mol Med (NATURE PUBLISHING GROUP, 2016-08-25)
      The centrosome is the major microtubule-organizing centre of many cells, best known for its role in mitotic spindle organization. How the proteins of the centrosome are accurately assembled to carry out its many functions remains poorly understood. The non-membranebound nature of the centrosome dictates that protein-protein interactions drive its assembly and functions. To investigate this massive macromolecular organelle, we generated a `domain-level' centrosome interactome using direct protein-protein interaction data from a focused yeast two-hybrid screen. We then used biochemistry, cell biology and the model organism Drosophila to provide insight into the protein organization and kinase regulatory machinery required for centrosome assembly. Finally, we identified a novel role for Plk4, the master regulator of centriole duplication. We show that Plk4 phosphorylates Cep135 to properly position the essential centriole component Asterless. This interaction landscape affords a critical framework for research of normal and aberrant centrosomes.
    • Centrosome loss results in an unstable genome and malignant prostate tumors

      Wang, Mengdie; Nagle, Raymond B; Knudsen, Beatrice S; Cress, Anne E; Rogers, Gregory C; Univ Arizona, Canc Ctr, Dept Cellular & Mol Med; Univ Arizona, Canc Ctr, Dept Pathol (NATURE PUBLISHING GROUP, 2019-09-02)
      Localized, nonindolent prostate cancer (PCa) is characterized by large-scale genomic rearrangements, aneuploidy, chromothripsis, and other forms of chromosomal instability (CIN), yet how this occurs remains unclear. A well-established mechanism of CIN is the overproduction of centrosomes, which promotes tumorigenesis in various mouse models. Therefore, we developed a single-cell assay for quantifying centrosomes in human prostate tissue. Surprisingly, centrosome loss-which has not been described in human cancer-was associated with PCa progression. By chemically or genetically inducing centrosome loss in nontumorigenic prostate epithelial cells, mitotic errors ensued, producing aneuploid, and multinucleated cells. Strikingly, transient or chronic centrosome loss transformed prostate epithelial cells, which produced highly proliferative and poorly differentiated malignant tumors in mice. Our findings suggest that centrosome loss could create a cellular crisis with oncogenic potential in prostate epithelial cells.