UFGI publication round-up week 5/29 and 6/5/17
Relationship between acute and chronic toxicity for prevalent organic pollutants in Vibrio fischeri based upon chemical mode of action.
Author information: Wang XH1, Fan LY1, Wang S1, Wang Y1, Yan LC1, Zheng SS1, Martyniuk CJ2, Zhao YH3.
Date of e-pub: June 2017
Abstract: Chemicals show diverse modes of action (MOAs) in aquatic organisms depending upon acute and chronic toxicity evaluations. Here, toxicity data for Vibrio fischeri involving 52 compounds for acute and chronic toxicity were used to determine the congruence of acute and chronic toxicity for assessing MOAs. Using toxic ratios, most of the compounds categorized into MOAs that included baseline, less inert or reactive compounds with acute toxicity were also categorized as baseline, less inert or reactive compounds with chronic toxicity. However, significantly different toxic effects were observed with acute and chronic toxicity for the reactive and specific-acting compounds. The acute-chronic toxic ratios were smaller and less variable for the baseline and less inert compounds, but were greater and more variable for the reactive and specific-acting compounds. Baseline and less inert compounds share same MOAs, but reactive and specific-acting compounds have different MOAs between acute and chronic toxicity. Bioconcentration processes cannot reach an equilibrium for highly hydrophilic and ionized compounds with short-term exposure, resulting in lower toxicity compared to long-term exposure. Pronounced differences for the antibiotics were not only due to the difference in bioconcentration, but also due to a predicted difference in MOAs during acute and chronic exposures.
Farm to Sensory Lab: Taste of Blueberry Fruit by Children and Adults.
Author information: Mennella JA1, Colquhoun TA2, Bobowski NK1, Olmstead JW3, Bartoshuk L4, Clark D2.
Date of e-pub: June 2017
Abstract: The average American child eats fewer fruits than recommended. Although taste is the primary motivator for food intake among children, little research has systematically measured children’s liking of fruit and determined whether their preferences differ from adults. We phenotyped 49 children and their mothers to determine: (1) their liking of the taste of 3 blueberry cultivars (“Arcadia,” “Keecrisp,” and “Kestrel”) from 2 harvests for which total soluble solids were determined using a handheld Brix refractometer; (2) the association between liking and blueberry sugar content; and (3) the most preferred level of fructose, one of the primary sugars in blueberry fruit. Multiple methods, identical for all participants, assessed which cultivar they liked best. Dietary intake, determined via 24-h dietary recall, revealed most children (73%) and adults (92%) did not meet dietary guidelines for fruit intake. We found that during the 1st harvest, Keecrisp was sweeter by 4° Brix than either Arcadia or Kestrel and was the cultivar most preferred by both children and adults. For the 2nd harvest, mothers liked each of the cultivars equally, but children preferred Arcadia, which was 2° Brix sweeter than the other 2 cultivars. Like other sugars, children’s most preferred concentration of fructose was significantly higher than that of adults. In sum, children appear to be more sensitive to smaller variations in sweetness than are adults. Identifying drivers of fruit preference and assessing children’s liking for whole fruits are important steps in developing strategies to increase fruit consumption among children.
Periorbital and Temporal Anatomy, “Targeted Fat Grafting,” and How a Novel Circulatory System in Human Peripheral Nerves and Brain May Help Avoid Nerve Injury and Blindness During Routine Facial Augmentation.
Author information: Pessa JE1, Kenkel JM1, Heldermon CD1.
Date of e-pub: June 2017
Abstract: N/A
Experimental Evolution with Caenorhabditis Nematodes.
Author information: Teotónio H1, Estes S2, Phillips PC3, Baer CF4,5.
Date of e-pub: June 2017
Abstract: The hermaphroditic nematode Caenorhabditis elegans has been one of the primary model systems in biology since the 1970s, but only within the last two decades has this nematode also become a useful model for experimental evolution. Here, we outline the goals and major foci of experimental evolution with C. elegans and related species, such as C. briggsae and C. remanei, by discussing the principles of experimental design, and highlighting the strengths and limitations of Caenorhabditis as model systems. We then review three exemplars of Caenorhabditis experimental evolution studies, underlining representative evolution experiments that have addressed the: (1) maintenance of genetic variation; (2) role of natural selection during transitions from outcrossing to selfing, as well as the maintenance of mixed breeding modes during evolution; and (3) evolution of phenotypic plasticity and its role in adaptation to variable environments, including host-pathogen coevolution. We conclude by suggesting some future directions for which experimental evolution with Caenorhabditis would be particularly informative.
Enrichment of IL-17A (+) IFN-γ (+) and IL-22 (+) IFN-γ (+)T cell Subsets Is Associated with Reduction of NKp44 (+) ILC3s in the Terminal Ileum of Crohn’s Disease Patients.
Author information: Li J1, Doty AL1, Tang Y1, Berrie D1, Iqbal A2, Tan SA2, Clare-Salzler MJ3, Wallet SM4, Glover SC1.
Date of e-pub: June 2017
Abstract: Crohn’s disease (CD) is a chronic inflammatory condition of the human gastrointestinal tract whose etiology remains largely unknown. Dysregulated adaptive immune responses and defective innate immunity both contribute to this process. In this study, we demonstrated that the IL-17A (+) IFN-γ (+) and IL-22 (+) IFN-γ (+) T cell subsets specifically accumulated in the inflamed terminal ileum of CD patients. These cells had higher expression of Ki-67 and were active cytokine producers. In addition, their proportions within both the IL-17A-producer and IL-22-producer populations were significantly increased. These data suggest that IL-17A (+) IFN-γ (+) and IL-22 (+) IFN-γ (+) T cell subsets might represent the pathogenic TH17 population in the context of intestinal inflammation for CD patients. In the innate immunity compartment we detected a dramatic alteration of both phenotype and function of the intestinal innate lymphoid cells (ILCs) that play an important role in the maintenance of mucosal homeostasis. In the inflamed gut the frequency of the NKp44 (-) CD117 (-) ILC1s subset was significantly increased while the frequency of NKp44 (+) ILC3s was reduced. Furthermore, the frequency of HLA-DR-expressing-NKp44 (+) ILC3s was also significantly reduced. Interestingly, the decrease in the NKp44 (+) ILC3s population was associated with an increase of pathogenic IL-17A (+) IFN-γ (+) and IL-22 (+) IFN-γ (+) T cell subsets in the adaptive compartment. This might suggest a potential link between NKp44 (+) ILC3s and the IL-17A (+) IFN-γ (+) and IL-22 (+) IFN-γ (+) T cell subsets in the terminal ileum of CD patients. This article is protected by copyright. All rights reserved.
An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence.
Author information: Martinez I1, Hayes KE2, Barr JA2, Harold AD2, Xie M3, Bukhari SIA4, Vasudevan S4, Steitz JA5,6,7, DiMaio D8,7,9,10.
Date of e-pub: June 2017
Abstract: The reversible state of proliferative arrest known as “cellular quiescence” plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNA-processing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.
Genetic Control of Floral Architecture: Insights into Improving Crop Yield.
Author information: Klee HJ1.
Date of e-pub: June 2017
Abstract: Selection of plants with traits that are beneficial for cultivation and consumption has been a common practice for thousands of years; however, combination of these traits can be detrimental too, for instance by leading to undesirable branching and yield loss in tomato. The findings from Soyk et al. in this issue of Cell help understand how to bypass such negative effects and improve crop productivity.
Consequences of Endogenous and Exogenous WNT Signaling for Development in the Preimplantation Bovine Embryo†.
Author information: Tribulo P1, da Silva Leão BC2, Lehloenya KC3, Mingoti GZ2, Hansen PJ1.
Date of e-pub: May 2017
Abstract: Although WNT signaling regulates several developmental processes, its specific role during preimplantation development remains unclear. The present aim was to evaluate the consequences of activation and inhibition of β-catenin (CTNNB1) dependent and -independent WNT signaling in the bovine preimplantation embryo. Activation of CTNNB1 mediated WNT signaling by the agonist 2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP) and a glycogen synthase kinase 3 (GSK3) inhibitor reduced development to the blastocyst stage. Moreover, the antagonist of WNT signaling, dickkopf-related protein 1 (DKK1), alleviated the negative effect of AMBMP on development via reduction of CTNNB1. Based on lack of an increase in labeling for phospho c-Jun N-terminal kinase, there was no evidence that DKK1 activated the planar cell polarity (PCP) pathway. Inhibition of secretion of endogenous WNTs did not affect development but increased the number of cells in the inner cell mass (ICM). In contrast, DKK1 did not affect number of ICM or trophectoderm (TE) cells, suggesting that embryo-derived WNTs regulate ICM proliferation through a mechanism independent of CTNNB1. In addition, DKK1 did not affect the number of cells positive for the transcription factor yes-associated protein 1 (YAP1) involved in TE formation. In fact, DKK1 decreased YAP1. In contrast, exposure of embryos to WNT7A improved blastocyst development, inhibited the PCP pathway, and did not affect amounts of CTNNB1. Results indicate that embryo-derived WNTs are dispensable for blastocyst formation but participate in the regulation of ICM proliferation, likely through a mechanism independent of CTNNB1. The response of embryos to AMBMP and WNT7A leads to the hypothesis that maternally-derived WNTs can play a positive or negative role in regulation of preimplantation development.
Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly.
Author information: Jian W1, Yan B1, Huang S2,3, Qiu Y4.
Date of e-pub: June 2017
Abstract: Histone acetyltransferases and histone deacetylases (HDACs) are important epigenetic coregulators. It has been thought that HDACs associate with corepressor complexes and repress gene transcription; however, in this study, we have found that PU.1-a key master regulator for hematopoietic self-renewal and lineage specification-requires HDAC activity for gene activation. Deregulated PU.1 gene expression is linked to dysregulated hematopoiesis and the development of leukemia. In this study, we used erythroid differentiation as a model to analyze how the PU.1 gene is regulated. We found that active HDAC1 is directly recruited to active PU.1 promoter in progenitor cells, whereas acetylated HDAC1, which is inactive, is on the silenced PU.1 promoter in differentiated erythroid cells. We then studied the mechanism of HDAC1-mediated activation. We discovered that HDAC1 activates PU.1 gene transcription via deacetylation of TATA-binding protein-associated factor 9 (TAF9), a component in the transcription factor IID (TFIID) complex. Treatment with HDAC inhibitor results in an increase in TAF9 acetylation. Acetylated TAF9 does not bind to the PU.1 gene promoter and subsequently leads to the disassociation of the TFIID complex and transcription repression. Thus, these results demonstrate a key role for HDAC1 in PU.1 gene transcription and, more importantly, uncover a novel mechanism of TFIID recruitment and gene activation.-Jian, W., Yan, B., Huang, S., Qiu, Y. Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly.
Complete Genomic Sequence of Dengue virus 1, Isolated from Plasma Collected from a Haitian Child in 2014.
Author information: Elbadry M1,2, White S1,2, Loeb J1,2, Tagliamonte M2,3, Salemi M2,4, Beau De Rochars JVM2,5, Okech B1,2, Morris G Jr2,6, Lednicky J7,2.
Date of e-pub: June 2017
Abstract: An outbreak of dengue fever followed a chikungunya fever outbreak in Haiti in 2014. We detected Dengue virus 1 (DENV-1) in plasma samples collected between May 2014 and February 2015. A representative isolate was fully sequenced, and phylogenetic analyses indicate that it groups within the genotype V South American and Caribbean DENV-1 clades.
Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion.
Author information: Tse LV1, Klinc KA1, Madigan VJ1,2, Castellanos Rivera RM1, Wells LF1, Havlik LP1,2, Smith JK3,4, Agbandje-McKenna M3,4, Asokan A5,2,6.
Date of e-pub: May 2017
Abstract: Preexisting neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) pose a major, unresolved challenge that restricts patient enrollment in gene therapy clinical trials using recombinant AAV vectors. Structural studies suggest that despite a high degree of sequence variability, antibody recognition sites or antigenic hotspots on AAVs and other related parvoviruses might be evolutionarily conserved. To test this hypothesis, we developed a structure-guided evolution approach that does not require selective pressure exerted by NAbs. This strategy yielded highly divergent antigenic footprints that do not exist in natural AAV isolates. Specifically, synthetic variants obtained by evolving murine antigenic epitopes on an AAV serotype 1 capsid template can evade NAbs without compromising titer, transduction efficiency, or tissue tropism. One lead AAV variant generated by combining multiple evolved antigenic sites effectively evades polyclonal anti-AAV1 neutralizing sera from immunized mice and rhesus macaques. Furthermore, this variant displays robust immune evasion in nonhuman primate and human serum samples at dilution factors as high as 1:5, currently mandated by several clinical trials. Our results provide evidence that antibody recognition of AAV capsids is conserved across species. This approach can be applied to any AAV strain to evade NAbs in prospective patients for human gene therapy.
The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity.
Author information: Gorman JA1, Hundhausen C2, Errett JS3,4, Stone AE3,4, Allenspach EJ1,5, Ge Y6, Arkatkar T1, Clough C1, Dai X1, Khim S1, Pestal K4, Liggitt D7, Cerosaletti K2, Stetson DB4, James RG1,5, Oukka M1,4,5, Concannon P6, Gale M Jr3,4, Buckner JH2, Rawlings DJ1,4,5.
Date of e-pub: May 2017
Abstract: The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1T946) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1T946 exhibited heightened basal and ligand-triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1T946 displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1T946 mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.
Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?
Author information: O’Kell AL1, Wasserfall C2, Catchpole B3, Davison LJ4, Hess RS5, Kushner JA6, Atkinson MA7.
Date of e-pub: June 2017
Abstract: Despite decades of research in humans and mouse models of disease, substantial gaps remain in our understanding of pathogenic mechanisms underlying the development of type 1 diabetes. Furthermore, translation of therapies from preclinical efforts capable of delaying or halting β-cell destruction has been limited. Hence, a pressing need exists to identify alternative animal models that reflect human disease. Canine insulin deficiency diabetes is, in some cases, considered to follow autoimmune pathogenesis, similar to NOD mice and humans, characterized by hyperglycemia requiring lifelong exogenous insulin therapy. Also similar to human type 1 diabetes, the canonical canine disorder appears to be increasing in prevalence. Whereas islet architecture in rodents is distinctly different from humans, canine pancreatic endocrine cell distribution is more similar. Differences in breed susceptibility alongside associations with MHC and other canine immune response genes parallel that of different ethnic groups within the human population, a potential benefit over NOD mice. The impact of environment on disease development also favors canine over rodent models. Herein, we consider the potential for canine diabetes to provide valuable insights for human type 1 diabetes in terms of pancreatic histopathology, impairment of β-cell function and mass, islet inflammation (i.e., insulitis), and autoantibodies specific for β-cell antigens.
Mary Tyler Moore (1936-2017): Diabetes Educator and Advocate.
Author information: Atkinson MA1, Nierras CR2.
Date of e-pub: June 2017
Abstract: N/A
Application of Genomic Estimation Methods of Inbreeding and Population Structure in an Arabian Horse Herd.
Author information: Al Abri MA1, König von Borstel U1, Strecker V1, Brooks SA1.
Date of e-pub: June 2017
Abstract: Horse breeders rely heavily on pedigrees for identification of ancestry in breeding stock. Inaccurate pedigrees may erroneously assign individuals to false lineages or breed memberships resulting in wrong estimates of inbreeding and coancestry. Moreover, discrepancies in pedigree records can lead breeders seeking to limit inbreeding into making misguided breeding decisions. Genome-wide SNPs provide a quantitative tool to aid in the resolution of lineage assignments and the calculation of genomic measures of relatedness. The aim of this project was to pilot a comparison between pedigree and genomic relatedness and inbreeding measures in a herd of 36 pedigreed Egyptian Arabian horses genotyped using the Equine SNP70 platform (Geneseek, Inc.). Moreover, we sought to estimate the minimum number of markers sufficient for genomic inbreeding calculations. Pedigree inbreeding values were moderately correlated with genomic inbreeding values (r = 0.406), whereas genomic relationships and pedigree relationships have a high correlation (r = 0.77). Although first degree relationships were successfully reconstructed, more distant relationships were difficult to resolve. Multi-dimensional scaling and clustering analysis agreed with within-herd pedigree information. In comparing the herd to a reference sample of United States, Polish, and Egyptian Arabian horses, the herd’s historically recorded Egyptian lineage was successfully recovered. We conclude that genomic estimates of inbreeding and relationships are superior to their pedigree counterparts. They can be thus utilized in conservation of valuable lines of livestock, and in breeds at risk for loss of genomic diversity. We also postulate a minimum of 2000 markers in linkage equilibrium to be used for inbreeding estimation.
A comprehensive analysis of myocardial substrate preference emphasizes the need for a synchronized fluxomic/metabolomic research design.
Author information: Ragavan M1, Kirpich A2,3, Fu X4, Burgess SC4,5, McIntyre LM2,3,6, Merritt ME7.
Date of e-pub: June 2017
Abstract: The heart oxidizes fatty acids, carbohydrates, and ketone bodies inside the tricarboxylic acid (TCA) cycle to generate the reducing equivalents needed for ATP production. Competition between these substrates makes it difficult to estimate the extent of pyruvate oxidation. Previously, hyperpolarized pyruvate detected propionate-mediated activation of carbohydrate oxidation, even in the presence of acetate. In this report, the optimal concentration of propionate for the activation of glucose oxidation was measured in mouse hearts perfused in Langendorff mode. This study was performed with a more physiologically relevant perfusate than the previous work. Increasing concentrations of propionate did not cause adverse effects on myocardial metabolism, as evidenced by unchanged O2 consumption, TCA cycle flux, and developed pressures. Propionate at 1 mM was sufficient to achieve significant increases in pyruvate dehydrogenase flux (3×), and anaplerosis (6×), as measured by isotopomer analysis. These results further demonstrate the potential of propionate as an aid for the correct estimation of total carbohydrate oxidative capacity in the heart. However, liquid chromotography/mass spectroscopy-based metabolomics detected large changes (~30-fold) in malate and fumarate pool sizes. This observation leads to a key observation regarding mass balance in the TCA cycle; flux through a portion of the cycle can be drastically elevated without changing the O2 consumption.
Dieldrin Augments mTOR Signaling and Regulates Genes Associated with Cardiovascular Disease in the Adult Zebrafish Heart (Danio rerio).
Author information: Slade L1, Cowie A1, Martyniuk CJ1, Kienesberger PC1, Pulinilkunnil T2.
Date of e-pub: June 2017
Abstract: Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiologic studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been adequately addressed to date given that these chemicals are detectable in human serum and are environmentally persistent; thus, individuals may show latent adverse effects in the cardiovascular system due to long-term, low-dose exposure over time. Our objective was to determine whether low-level exposure to dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to dieldrin treatment and show that dieldrin affects gene networks in the heart that are associated with processes related to cardiovascular disease, specifically cardiac arrest and ventricular fibrillation. We report that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by dieldrin whereas transcripts related to lysosomal function are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our results demonstrate that dieldrin constitutively activates Akt/mTOR signaling and downregulates lysosomal genes, participating in autophagy. Our data demonstrate that dieldrin induces genes associated with cardiovascular dysfunction and compromised lysosomal physiology, thereby identifying a novel mechanism for pesticide-induced cardiotoxicity.
Myotonic dystrophy: approach to therapy.
Author information: Thornton CA1, Wang E2, Carrell EM3.
Date of e-pub: June 2017
Abstract: Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG triplet repeat in DMPK, whereas DM type 2 is caused by expansion of a CCTG tetramer repeat in CNBP. In both cases the DM mutations lead to expression of dominant-acting RNAs. Studies of RNA toxicity have now revealed novel mechanisms and new therapeutic targets. Preclinical data have suggested that RNA dominance is responsive to therapeutic intervention and that DM therapy can be approached at several different levels. Here we review recent efforts to alleviate RNA toxicity in DM.
F-Box Protein XREP-4 Is a New Regulator of the Oxidative Stress Response in Caenorhabditis elegans.
Author information: Wu CW1,2, Wang Y1,2, Choe KP3,4.
Date of e-pub: June 2017
Abstract: The transcription factor SKN-1 (Skinhead family member-1) in Caenorhabditis elegans is a homolog of the mammalian Nrf-2 protein and functions to promote oxidative stress resistance and longevity. SKN-1 mediates protection from reactive oxygen species (ROS) via the transcriptional activation of genes involved in antioxidant defense and phase II detoxification. Although many core regulators of SKN-1 have been identified, much remains unknown about this complex signaling pathway. We carried out an ethyl methanesulfonate (EMS) mutagenesis screen and isolated six independent mutants with attenuated SKN-1-dependent gene activation in response to acrylamide. All six were found to contain mutations in F46F11.6/xrep-4 (xenobiotics response pathways-4), which encodes an uncharacterized F-box protein. Loss of xrep-4 inhibits the skn-1-dependent expression of detoxification genes in response to prooxidants and decreases survival of oxidative stress, but does not shorten life span under standard culture conditions. XREP-4 interacts with the ubiquitin ligase component SKR-1 and the SKN-1 principal repressor WDR-23, and knockdown of xrep-4 increases nuclear localization of a WDR-23::GFP fusion protein. Furthermore, a missense mutation in the conserved XREP-4 F-box domain that reduces interaction with SKR-1 but not WDR-23 strongly attenuates SKN-1-dependent gene activation. These results are consistent with XREP-4 influencing the SKN-1 stress response by functioning as a bridge between WDR-23 and the ubiquitin ligase component SKR-1.
Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia.
Author information: Kim YH1, Kim MJ2,3, Choe SW1,4, Sprecher D5, Lee YJ3, P Oh S1,5.
Date of e-pub: June 2017
Abstract: Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding.
Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.
Overexpression of the X-Linked Inhibitor of Apoptosis Protects Against Retinal Degeneration in a Feline Model of Retinal Detachment.
Author information: Wassmer SJ1, Leonard BC2,3,4, Coupland SG1,2,3,4, Baker AN3, Hamilton J4, Hauswirth WW5, Tsilfidis C1,2,3,4.
Date of e-pub: June 2017
Abstract: Retinal detachment is an acute disorder in humans that is caused by trauma or disease, and it can often lead to permanent visual deficits that result from the death of photoreceptors in the retina. The final pathway for photoreceptor cell death is apoptosis and necroptosis. The X-linked inhibitor of apoptosis (XIAP) has been shown to block both of these cell death pathways. This study tested the effects of XIAP on photoreceptor survival in a feline model of retinal detachment. The study was performed in 12 cats, divided into two experimental groups. Six animals received a subretinal injection of adeno-associated virus (AAV) carrying XIAP, and six animals received AAV carrying green fluorescent protein (GFP) as a control. Three weeks after viral delivery, retinas were detached by injecting C3F8 gas into the subretinal space. Optical coherence tomography revealed that the retinal detachments resolved within 3-6 weeks as the gas was slowly resorbed. Analysis of histological sections through the plane of the detachment showed significant preservation of the photoreceptor layer in AAV-XIAP-treated animals compared to AAV-GFP-treated animals at 9 weeks after the detachment. XIAP-treated detached retinas were similar to intact controls. These studies support the potential for XIAP therapy in the treatment of human retinal detachment.
Convergence of Domain Architecture, Structure, and Ligand Affinity in Animal and Plant RNA-Binding Proteins.
Author information: Dias R1, Manny A2, Kolaczkowski O2, Kolaczkowski B2,3.
Date of e-pub: June 2017
Abstract: Reconstruction of ancestral protein sequences using phylogenetic methods is a powerful technique for directly examining the evolution of molecular function. Although ancestral sequence reconstruction (ASR) is itself very efficient, downstream functional, and structural studies necessary to characterize when and how changes in molecular function occurred are often costly and time-consuming, currently limiting ASR studies to examining a relatively small number of discrete functional shifts. As a result, we have very little direct information about how molecular function evolves across large protein families. Here we develop an approach combining ASR with structure and function prediction to efficiently examine the evolution of ligand affinity across a large family of double-stranded RNA binding proteins (DRBs) spanning animals and plants. We find that the characteristic domain architecture of DRBs-consisting of 2-3 tandem double-stranded RNA binding motifs (dsrms)-arose independently in early animal and plant lineages. The affinity with which individual dsrms bind double-stranded RNA appears to have increased and decreased often across both animal and plant phylogenies, primarily through convergent structural mechanisms involving RNA-contact residues within the β1-β2 loop and a small region of α2. These studies provide some of the first direct information about how protein function evolves across large gene families and suggest that changes in molecular function may occur often and unassociated with major phylogenetic events, such as gene or domain duplications.
Is homoploid hybrid speciation that rare? An empiricist’s view.
Author information: Nieto Feliner G1, Álvarez I1, Fuertes-Aguilar J1, Heuertz M2, Marques I3,4, Moharrek F5, Piñeiro R6, Riina R1, Rosselló JA7, Soltis PS8, Villa-Machío I1.
Date of e-pub: June 2017
Abstract: N/A
Evolutionary and domestication history of Cucurbita (pumpkin and squash) species inferred from 44 nuclear loci.
Author information: Kates HR1, Soltis PS2, Soltis DE3.
Date of e-pub: June 2017
Abstract: Phylogenetics can facilitate the study of plant domestication by resolving sister relationships between crops and their wild relatives, thereby identifying the ancestors of cultivated plants. Previous phylogenetic studies of the six Cucurbita crop lineages (pumpkins and squashes) and their wild relatives suggest histories of deep coalescence that complicate uncovering the genetic origins of the six crop taxa. We investigated the evolution of wild and domesticated Cucurbita using the most comprehensive and robust molecular-based phylogeny for Cucurbita to date based on 44 loci derived from introns of single-copy nuclear genes. We discovered novel relationships among Cucurbita species and recovered the first Cucurbita tree with well-supported resolution within species. Cucurbita comprises a clade of mesophytic annual species that includes all six crop taxa and a grade of xerophytic perennial species that represent the ancestral xerophytic habit of the genus. Based on phylogenetic resolution within-species we hypothesize that the magnitude of domestication bottlenecks varies among Cucurbita crop lineages. Our phylogeny clarifies how wild Cucurbita species are related to the domesticated taxa. We find close relationships between two wild species and crop lineages not previously identified. Expanded geographic sampling of key wild species is needed for improved understanding of the evolution of domesticated Cucurbita.
Arsenic uptake by lettuce from As-contaminated soil remediated with Pteris vittata and organic amendment.
Author information: de Oliveira LM1, Suchismita D2, Gress J3, Rathinasabapathi B4, Chen Y5, Ma LQ6.
Date of e-pub: June 2017
Abstract: Leaching of inorganic arsenic (As) from chromated copper arsenate (CCA)-treated wood may elevate soil As levels. Thus, an environmental concern arises regarding As accumulation in vegetables grown in these soils. In this study, a greenhouse experiment was conducted to investigate the ability of As-hyperaccumulator P. vittata and organic amendments in reducing As uptake by lettuce (Lactuca sativa) from a soil contaminated from CCA-treated wood (63.9 mg kg-1 As). P. vittata was grown for 150 d in a CCA-contaminated soil amended with biochar, activated carbon or coffee grounds at 1%, followed by lettuce for another 55 d. After harvest, plant biomass and As concentrations in plant and soil were determined. The presence of P. vittata reduced As content in lettuce by 21% from 27.3 to 21.5 mg kg-1 while amendment further reduced As in lettuce by 5.6-18%, with activated C being most effective. Our data showed that both P. vittata and organic amendments were effective in reducing As concentration in lettuce. Though no health-based standard for As in vegetables exists in USA, care should be taken when growing lettuce in contaminated soils. Our data showed that application of organic amendments with P. vittata reduced As hazards in CCA-contaminated soils.
Molecular phylogeny of extant Holothuroidea (Echinodermata).
Author information: Miller AK1, Kerr AM2, Paulay G3, Reich M4, Wilson NG5, Carvajal JI5, Rouse GW6.
Date of e-pub: June 2017
Abstract: Sea cucumbers (Holothuroidea) are a morphologically diverse, ecologically important, and economically valued clade of echinoderms; however, the understanding of the overall systematics of the group remains controversial. Here, we present a phylogeny of extant Holothuroidea assessed with maximum parsimony, maximum likelihood, and Bayesian approaches using approximately 4.3kb of mt- (COI, 16S, 12S) and nDNA (H3, 18S, 28S) sequences from 82 holothuroid terminals representing 23 of the 27 widely-accepted family-ranked taxa. Currently five holothuroid taxa of ordinal rank are accepted. We find that three of the five orders are non-monophyletic, and we revise the taxonomy of the groups accordingly. Apodida is sister to the rest of Holothuroidea, here considered Actinopoda. Within Actinopoda, Elasipodida in part is sister to the remaining Actinopoda. This latter clade, comprising holothuroids with respiratory trees, is now called Pneumonophora. The traditional Aspidochirotida is paraphyletic, with representatives from three orders (Molpadida, Dendrochirotida, and Elasipodida in part) nested within. Therefore, we discontinue the use of Aspidochirotida and instead erect Holothuriida as the sister group to the remaining Pneumonophora, here termed Neoholothuriida. We found four well-supported major clades in Neoholothuriida: Dendrochirotida, Molpadida and two new clades, Synallactida and Persiculida. The mapping of traditionally-used morphological characters in holothuroid systematics onto the phylogeny revealed marked homoplasy in most characters demonstrating that further taxonomic revision of Holothuroidea is required. Two time-tree analyses, one based on calibrations for uncontroversial crown group dates for Eleutherozoa, Echinozoa and Holothuroidea and another using these calibrations plus four more from within Holothuroidea, showed major discrepancies, suggesting that fossils of Holothuroidea may need reassessment in terms of placing these forms with existing crown clades.
Evolutionary Conservation of ABA Signaling for Stomatal Closure.
Author information: Cai S1,2,3,4,5,6,7,8,9,10, Chen G1,2,3,4,5,6,7,8,9,10, Wang Y1,2,3,4,5,6,7,8,9,10, Huang Y1,2,3,4,5,6,7,8,9,10, Marchant DB1,2,3,4,5,6,7,8,9,10, Wang Y1,2,3,4,5,6,7,8,9,10, Yang Q1,2,3,4,5,6,7,8,9,10, Dai F1,2,3,4,5,6,7,8,9,10, Hills A1,2,3,4,5,6,7,8,9,10, Franks PJ1,2,3,4,5,6,7,8,9,10, Nevo E1,2,3,4,5,6,7,8,9,10, Soltis DE1,2,3,4,5,6,7,8,9,10, Soltis PS1,2,3,4,5,6,7,8,9,10, Sessa E1,2,3,4,5,6,7,8,9,10, Wolf PG1,2,3,4,5,6,7,8,9,10, Xue D1,2,3,4,5,6,7,8,9,10, Zhang G1,2,3,4,5,6,7,8,9,10, Pogson BJ1,2,3,4,5,6,7,8,9,10, Blatt MR1,2,3,4,5,6,7,8,9,10, Chen ZH11,12,13,14,15,16,17,18,19,20.
Date of e-pub: June 2017
Abstract: Abscisic acid (ABA)-driven stomatal regulation reportedly evolved after the divergence of ferns, during the early evolution of seed plants approximately 360 million years ago. This hypothesis is based on the observation that the stomata of certain fern species are unresponsive to ABA, but exhibit passive hydraulic control. However, ABA-induced stomatal closure was detected in some mosses and lycophytes. Here, we observed that a number of ABA signaling and membrane transporter protein families diversified over the evolutionary history of land plants. The aquatic ferns Azolla filiculoides and Salvinia cucullata have representatives of 23 families of proteins orthologous to those of Arabidopsis (Arabidopsis thaliana) and all other land plant species studied. Phylogenetic analysis of the key ABA signaling proteins indicates an evolutionarily conserved stomatal response to ABA. Moreover, comparative transcriptomic analysis has identified a suite of ABA-responsive genes that differentially expressed in a terrestrial fern species, Polystichum proliferum These genes encode proteins associated with ABA biosynthesis, transport, reception, transcription, signaling, and ion and sugar transport, which fit the general ABA signaling pathway constructed from Arabidopsis and Hordeum vulgare The retention of these key ABA-responsive genes could have had a profound effect on the adaptation of ferns to dry conditions. Furthermore, stomatal assays have shown the primary evidence for ABA-induced closure of stomata in two terrestrial fern species Pproliferum and Nephrolepis exaltata In summary, we report, to our knowledge, new molecular and physiological evidence for the presence of active stomatal control in ferns.
Development and Assessment of a Novel Canine Ex Vivo Corneal Model.
Author information: Proietto LR1, Whitley RD1, Brooks DE1, Schultz GE2, Gibson DJ2, Berkowski WM Jr1, Salute ME1, Plummer CE1.
Date of e-pub: June 2017
Abstract:
To develop a novel ex vivo extended culture model of canine corneal epithelial cell wound healing.
Canine corneoscleral rims (CSR) were obtained and, after preparation for culture, were placed on a nutating scaffold and incubated in physiological conditions. In experiment 1, eight CSR in a serum-containing antimicrobial-fortified medium were monitored for epithelial integrity and bacterial infection up to 28 days in culture. CSR were assessed histologically at the end of the culture period end points 0, 7, 14, and 28 days with accompanying scanning electron microscopic (SEM) and transmission electron microscopic (TEM) evaluation. Samples for microbial culture were obtained at days 0, 3, 7, 14, and 28. In experiment 2, uniform 8-mm-diameter superficial corneal epithelial wounds were created and monitored for re-epithelialization in the same culture conditions or in a serum-free protein equivalent medium, with four CSR per group. Standardized digital images were obtained with cobalt filter at the time of fluorescein staining and media change every six hours. Image J imaging software was used to measure the area of fluorescein retention. Re-epithelialization rates were calculated and CSR then fixed for immunohistochemistry (IHC).
All corneas survived to end points as described in experiment 1 with no evidence of contamination or compromised epithelial integrity. Histologically, a multilayered epithelium was maintained and corneal edema was not appreciated until day 14. SEM examination revealed epithelial cell layer confluence and migrating epithelial cells of normal cellular morphology with normal cell-cell interactions on TEM. In experiment 2, all eight corneas healed with a healing rate of 0.702 ± 0.130 mm2/h (1.25 mm/day epithelial cell migration rate) and were positive in IHC evaluation for markers of corneal fibrosis.
This ex vivo canine corneal wound healing model is an appropriate and clinically relevant tool for assessment and modulation of epithelial wound healing.
NOTE: These abstracts were retrieved from the U.S. National Library of Medicine website managed in collaboration with the U.S. National Library of Medicine