UFGI publication round-up week 6/26 and 7/3/17
Life-extending dietary restriction and ovariectomy each increase leucine oxidation and alter leucine allocation in grasshoppers.
Author information: Hatle JD1, Awan A2, Nicholas J2, Koch R2, Vokrri JR2, McCue MD3, Williams CM4, Davidowitz G5, Hahn DA6.
Date of e-pub: June 2017
Abstract: Reduced reproduction and dietary restriction each extend lifespan in many animal models, but possible contributions of nutrient oxidation and allocation are largely unknown. Ovariectomy and eating 70% of ad libitum-feeding each extend lifespan in lubber grasshoppers. When feeding levels between the two groups are matched, ovariectomy increases fat and protein storage while dietary restriction reduces fat storage. Because of these disparities in nutrient investment, metabolism may differ between these two life-extending treatments. Therefore, we examined the allocation and organismal oxidation of one representative of each macronutrient class: leucine, oleic acid, and glucose. Ovariectomy and dietary restriction each increased oxidation of dietary leucine. Dietary leucine may play a special role in aging because amino acids stimulate cellular growth. Speeding oxidation of leucine may attenuate cellular growth. Allocation of leucine to muscle was the clearest difference between ovariectomy and dietary restriction in this study. Ovariectomy reduced allocation of leucine to femur muscle, whereas dietary restriction increased allocation of leucine to femur muscle. This allocation likely corresponds to muscle maintenance for locomotion, suggesting dietary restriction increases support for locomotion, perhaps to search for food. Last, ovariectomy decreased oxidation of dietary oleic acid and glucose, perhaps to save them for storage, but the site of storage is unclear. This study suggests that the oxidation of branched-chain amino acids may be an underappreciated mechanism underlying lifespan extension.
Physiological, molecular and ultrastructural analyses during ripening and over-ripening of banana (Musa spp., AAA group, Cavendish subgroup) fruit suggest characteristics of programmed cell death.
Author information: Ramírez-Sánchez M1, Huber DJ1, Vallejos CE1, Kelley K2.
Date of e-pub: June 2017
Abstract: Programmed cell death (PCD) is a part of plant development that has been studied for petal senescence and vegetative tissue but has not been thoroughly investigated for fleshy fruits. The purpose of this research was to examine ripening and over-ripening in banana fruit to determine if there were processes in common to previously described PCD.
Loss of cellular integrity (over 40 %) and development of senescence related dark spot (SRDS) occurred after day 8 in banana peel. Nuclease and protease activity in the peel increased during ripening starting from day 2, and decreased during over-ripening. The highest activity was for proteases and nucleases with apparent molecular weights of 86 kDa and 27 kDa, respectively. Images of SRDS showed shrinkage of the upper layers of cells, visually suggesting cell death. Decrease of electron dense areas was evident in TEM micrographs of nuclei.
This study shows for the first time that ripening and over-ripening of banana peel share physiological and molecular processes previously described in plant PCD. SRDS could represent a morphotype of PCD that characterizes a structural and biochemical failure in the upper layers of the peel, thereafter spreading to lower and adjacent layers of cells.
My Child Is Islet Autoantibody Positive: Impact on Parental Anxiety.
Author information: Bennett Johnson S1, Lynch KF2, Roth R3,4, Schatz D5; TEDDY Study Group.
Date of e-pub: June 2017
Abstract: To assess parent anxiety in response to genetic and islet autoantibody (IA) testing in children at increased genetic risk for type 1 diabetes followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study.
Parent anxiety about TEDDY children’s risk was assessed with the State Anxiety Inventory (SAI). Parents completed the SAI when the child was 3, 6, and 15 months old and annually thereafter. Children were tested for IA every 3 months for 4 years and every 6 months thereafter. Parent SAI scores of 6,799 children followed with IA testing for at least 1 and up to 6 years were examined.
At study inception, parents showed high levels of anxiety in response to their child’s increased genetic type 1 diabetes risk; mothers were more anxious than fathers, and parents with diabetes in the family were more anxious than parents with no family history. In response to repeated IA-negative (IA-) test results, parent anxiety declined to normal levels. Anxiety increased in parents faced with an IA-positive (IA+) test result. Parents faced with two or more types of IA+ test results showed particularly high levels of anxiety (all P < 0.001).
Infant genetic screening for type 1 diabetes raises parent anxiety when the child is at increased risk, but anxiety dissipates over time in cases of repeated IA- results. IA+ results heighten parent anxiety, and parents faced with two or more types of IA+ results may experience considerable anxiety for longer periods.
Genetic dissection of the Arabidopsis spaceflight transcriptome: Are some responses dispensable for the physiological adaptation of plants to spaceflight?
Author information: Paul AL1, Sng NJ1, Zupanska AK1, Krishnamurthy A1, Schultz ER1, Ferl RJ1,2.
Date of e-pub: June 2017
Abstract: Experimentation on the International Space Station has reached the stage where repeated and nuanced transcriptome studies are beginning to illuminate the structural and metabolic differences between plants grown in space compared to plants on the Earth. Genes that are important in establishing the spaceflight responses are being identified, their roles in spaceflight physiological adaptation are increasingly understood, and the fact that different genotypes adapt differently is recognized. However, the basic question of whether these spaceflight responses are actually required for survival has yet to be posed, and the fundamental notion that spaceflight responses may be non-adaptive has yet to be explored. Therefore the experiments presented here were designed to ask if portions of the plant spaceflight response can be genetically removed without causing loss of spaceflight survival and without causing increased stress responses. The CARA experiment compared the spaceflight transcriptome responses in the root tips of two Arabidopsis ecotypes, Col-0 and WS, as well as that of a PhyD mutant of Col-0. When grown with the ambient light of the ISS, phyD plants displayed a significantly reduced spaceflight transcriptome response compared to Col-0, suggesting that altering the activity of a single gene can actually improve spaceflight adaptation by reducing the transcriptome cost of physiological adaptation. The WS genotype showed an even simpler spaceflight transcriptome response in the ambient light of the ISS, more broadly indicating that the plant genotype can be manipulated to reduce the cost of spaceflight adaptation, as measured by transcriptional response. These differential genotypic responses suggest that genetic manipulation could further reduce, or perhaps eliminate the metabolic cost of spaceflight adaptation. When plants were germinated and then left in the dark on the ISS, the WS genotype actually mounted a larger transcriptome response than Col-0, suggesting that the in-space light environment affects physiological adaptation, which implies that manipulating the local habitat can also substantially impact the metabolic cost of spaceflight adaptation.
Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy.
Author information: Sicot G1, Servais L2, Dinca DM1, Leroy A3, Prigogine C3, Medja F1, Braz SO1, Huguet-Lachon A1, Chhuon C4, Nicole A1, Gueriba N1, Oliveira R5, Dan B6, Furling D7, Swanson MS5, Guerrera IC4, Cheron G3, Gourdon G8, Gomes-Pereira M9.
Date of e-pub: June 2017
Abstract: Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.
Functional interrelationship between TFII-I and E2F transcription factors at specific cell cycle gene loci.
Author information: Shen Y1, Nar R1, Fan AX1, Aryan M1, Hossain MA1, Gurumurthy A1, Wassel PC1, Tang M1, Lu J1, Strouboulis J2, Bungert J1.
Date of e-pub: June 2017
Abstract: Transcription factor TFII-I is a multifunctional protein implicated in the regulation of cell cycle and stress-response genes. Previous studies have shown that a subset of TFII-I associated genomic sites contained DNA-binding motifs for E2F family transcription factors. We analyzed the co-association of TFII-I and E2Fs in more detail using bioinformatics, chromatin immunoprecipitation, and co-immunoprecipitation experiments. The data show that TFII-I interacts with E2F transcription factors. Furthermore, TFII-I, E2F4, and E2F6 interact with DNA-regulatory elements of several genes implicated in the regulation of the cell cycle, including DNMT1, HDAC1, CDKN1C and CDC27. Inhibition of TFII-I expression led to a decrease in gene expression and in the association of E2F4 and E2F6 with these gene loci in human erythroleukemia K562 cells. Finally, TFII-I deficiency reduced the proliferation of K562 cells and increased the sensitivity towards doxorubicin toxicity. The results uncover novel interactions between TFII-I and E2Fs and suggest that TFII-I mediates E2F function at specific cell cycle genes. This article is protected by copyright. All rights reserved.
Hepatocyte-specific HNF4α/miR-122 pathway contributes to the iron-overload mediated hepatic inflammation.
Author information: Li M1, Tang Y1, Wu L1, Mo F1, Wang X1, Li H1, Qi R1, Zhang H1, Srivastava A2, Ling C3.
Date of e-pub: June 2017
Abstract: Hepatic iron-overload (IO) is one of the major complications of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, decrease of microRNA-122 was observed in a genetic knockout (Hfe-/-) mouse model of IO. Since hepatocyte-enriched miR-122 is known as a key regulator of multiple hepatic pathways including inflammation, it is of interest whether hepatocyte directly contributes to the IO-mediated hepatic inflammation. Here, we report that IO induces similar inflammatory responses in both human primary hepatocytes and Thd-1 derived macrophages. In the mice liver, IO resulted in altered expression of not only inflammatory genes, but also more than 230 genes, which are known to be targets of the microRNA-122. In addition, both iron-dextran injection and 3% carbonyl iron-containing diet led to up-regulation of hepatic inflammation, which is associated with significant reduction of HNF4α and its downstream target microRNA-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophage is not the only target of IO. Most importantly, overexpression of microRNA-122 in a hepatocyte-specific manner rescued the IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in the IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major haemoglobinopathy.
Bacterial Nucleotidyl Cyclase Inhibits Host Innate Immune Response through Suppressing TAK1 Activation.
Author information: He C1, Zhou Y1, Liu F1, Liu H1, Tan H2, Jin S2,3, Wu W2, Ge B4.
Date of e-pub: June 2017
Abstract: Exoenzyme Y (ExoY) is a type III secretion system effector found in 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY is a soluble nucleotidyl cyclase that increases the cytoplasmic levels of nucleoside 3′ , 5′ -cyclic monophosphates (cNMPs) to mediate endothelial Tau phosphorylation and permeability, its functional role in the innate immune response is still poorly understood. Transforming growth factor β activated kinase-1 (TAK1) is critical for mediating Toll-like receptor (TLR) signaling and subsequent activation of NF-κB and AP-1, which are transcriptional activators of innate immunity. Here, we report that ExoY inhibits proinflammatory cytokine production through suppressing the activation of TAK1 as well as downstream NF-κB and MAP kinases. Mice infected with ExoY-deficient P. aeruginosa had higher TNF and IL-6 levels, more neutrophil recruitment, and a lower bacterial load in lung tissue compared to mice infected with wild-type P. aeruginosa Taken together, our findings identify a previously unknown mechanism by which P. aeruginosa ExoY inhibits the host innate immune response.
Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome.
Author information: Hirschtritt ME1, Darrow SM1, Illmann C2, Osiecki L2, Grados M3, Sandor P4, Dion Y5, King RA6, Pauls D2, Budman CL7, Cath DC8, Greenberg E2, Lyon GJ9, Yu D2, McGrath LM10, McMahon WM11, Lee PC12, Delucchi KL1, Scharf JM2, Mathews CA13.
Date of e-pub: June 2017
Abstract: The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families.
OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed.
EFA yielded a 2-factor model for ADHD and an 8-factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (⩾50% for all disorders).
Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders.
Intake of energy and protein is associated with overweight risk at age 5.5 years: Results from the prospective TEDDY study.
Author information: Beyerlein A1,2, Uusitalo UM3, Virtanen SM4,5,6,7, Vehik K3, Yang J3, Winkler C1,2, Kersting M8, Koletzko S9, Schatz D10, Aronsson CA11, Elding Larsson H11, Krischer JP3, Ziegler AG1,2, Norris JM12, Hummel S1,2; TEDDY Study Group.
Date of e-pub: June 2017
Abstract: The associations of energy, protein, carbohydrate, and fat intake with weight status up to the age of 5.5 years were prospectively assessed in The Environmental Determinants of Diabetes in the Young (TEDDY) study.
Food record data (over 3 days) and BMI measurements between 0.25 and 5.5 years were available from 5,563 children with an increased genetic risk for type 1 diabetes followed from shortly after birth. Odds ratios (ORs) were calculated for overweight and obesity by previous intake of energy, protein, carbohydrate, and fat with adjustment for potential confounders.
Having overweight or obesity at the age of 5.5 years was positively associated with mean energy intake in previous age intervals (e.g., adjusted OR [95% CI] for overweight: 1.06 [1.04-1.09] per 100 kcal intake at the age of 4.5-5.0 years) and with protein intake after the age of 3.5 and 4.5 years, respectively (e.g., adjusted OR for overweight: 1.06 [1.03-1.09] per 1% of energy intake at the age of 4.5-5.0 years). The respective associations with carbohydrate and fat intake were less consistent.
These findings indicate that energy and protein intake are positively associated with increased risk for overweight in childhood but yield no evidence for potential programming effects of protein intake in infancy.
Autism Spectrum Symptoms in a Tourette’s Disorder Sample.
Author information: Darrow SM1, Grados M2, Sandor P3, Hirschtritt ME1, Illmann C4, Osiecki L4, Dion Y5, King R6, Pauls D4, Budman CL7, Cath DC8, Greenberg E4, Lyon GJ9, McMahon WM10, Lee PC11, Delucchi KL1, Scharf JM12, Mathews CA13.
Date of e-pub: July 2017
Abstract: Tourette’s disorder (TD) and autism spectrum disorder (ASD) share clinical features and possibly an overlapping etiology. The aims of this study were to examine ASD symptom rates in participants with TD, and to characterize the relationships between ASD symptom patterns and TD, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD).
Participants with TD (n = 535) and their family members (n =234) recruited for genetic studies reported TD, OCD, and ADHD symptoms and completed the Social Responsiveness Scale Second Edition (SRS), which was used to characterize ASD symptoms.
SRS scores in participants with TD were similar to those observed in other clinical samples but lower than in ASD samples (mean SRS total raw score = 51; SD = 32.4). More children with TD met cut-off criteria for ASD (22.8%) than adults with TD (8.7%). The elevated rate in children was primarily due to high scores on the SRS Repetitive and Restricted Behaviors (RRB) subscale. Total SRS scores were correlated with TD (r = 0.27), OCD (r = 0.37), and ADHD (r = 0.44) and were higher among individuals with OCD symptom-based phenotypes than for those with tics alone.
Higher observed rates of ASD among children affected by TD may in part be due to difficulty in discriminating complex tics and OCD symptoms from ASD symptoms. Careful examination of ASD-specific symptom patterns (social communication vs. repetitive behaviors) is essential. Independent of ASD, the SRS may be a useful tool for identifying patients with TD with impairments in social communication that potentially place them at risk for bullying and other negative sequelae.
Circular Bivalent Aptamers Enable in Vivo Stability and Recognition.
Author information: Kuai H1, Zhao Z1, Mo L1, Liu H1, Hu X1, Fu T1, Zhang X1, Tan W1,2.
Date of e-pub: June 2017
Abstract: Aptamers are powerful candidates for molecular imaging and targeted therapy of cancer based on such appealing features as high binding affinity, high specificity, site-specific modification and rapid tumor penetration. However, aptamers are susceptible to plasma exonucleases in vivo. This seriously affects their in vivo applications. To overcome this key limitation, we herein report the design and development of circular bivalent aptamers. Systematic studies reveal that cyclization of aptamers can improve thermal stability, nuclease resistance and binding affinity. In vivo fluorescence imaging further validates the efficient accumulation and retention of circular bivalent aptamers in tumors compared to “mono-aptamers”. Therefore, this study provides a simple and efficient strategy to boost in vivo aptamer applications in cancer diagnosis and therapy.
Artificial Base zT as Functional “Element” for Constructing Photoresponsive DNA Nanomolecules.
Author information: Wang R1,2, Jin C1, Zhu X1, Zhou L1, Xuan W1, Liu Y1,2, Liu Q1, Tan W1,2.
Date of e-pub: June 2017
Abstract: In contrast to small molecules, DNA and RNA macromolecules can be accurately formulated with base “elements” abbreviated as A, T, U, C, and G. However, the development of functionally artificial bases can result in the generation of new biomaterials with unique properties and applications. Therefore, we herein report the design and synthesis of a photoresponsive base as a new functional or molecular “element” for constructing DNA nanomolecules. The new base is made by fusion of an azobenzene with a natural T base (zT). zT, a new molecular element, is not only the most size-expanded T analogue but also a photoresponsive base capable of specific self-assembly through hydrogen bonding. Our results showed that stable and selective self-assembly of double-stranded DNAs occurred through zT-A base pairing, but it could still be efficiently dissociated by light irradiation. The photoresponsive DNA bases will provide the versatility required for constructing desired DNA nanomolecules and nanodevices.
Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.
Author information: Zewinger S1, Kleber ME2, Tragante V3, McCubrey RO4, Schmidt AF5, Direk K5, Laufs U6, Werner C6, Koenig W7, Rothenbacher D8, Mons U9, Breitling LP9, Brenner H10, Jennings RT1, Petrakis I1, Triem S1, Klug M1, Filips A1, Blankenberg S11, Waldeyer C11, Sinning C11, Schnabel RB11, Lackner KJ12, Vlachopoulou E13, Nygård O14, Svingen GFT15, Pedersen ER16, Tell GS17, Sinisalo J18, Nieminen MS18, Laaksonen R19, Trompet S20, Smit RAJ20, Sattar N21, Jukema JW22, Groesdonk HV23, Delgado G24, Stojakovic T25, Pilbrow AP26, Cameron VA26, Richards AM27, Doughty RN28, Gong Y29, Cooper-DeHoff R29, Johnson J29, Scholz M30, Beutner F31, Thiery J32, Smith JG33, Vilmundarson RO34, McPherson R34, Stewart AFR34, Cresci S35, Lenzini PA36, Spertus JA37, Olivieri O38, Girelli D38, Martinelli NI38, Leiherer A39, Saely CH39, Drexel H40, Mündlein A41, Braund PS42, Nelson CP42, Samani NJ42, Kofink D3, Hoefer IE43, Pasterkamp G43, Quyyumi AA44, Ko YA44, Hartiala JA45, Allayee H45, Tang WHW46, Hazen SL46, Eriksson N47, Held C47, Hagström E47, Wallentin L47, Åkerblom A47, Siegbahn A48, Karp I49, Labos C50, Pilote L51, Engert JC50, Brophy JM50, Thanassoulis G50, Bogaty P52, Szczeklik W53, Kaczor M53, Sanak M53, Virani SS54, Ballantyne CM55, Lee VV56, Boerwinkle E57, Holmes MV58, Horne BD4, Hingorani A5, Asselbergs FW59, Patel RS5; GENIUS-CHD consortium, Krämer BK24, Scharnagl H25, Fliser D1, März W60, Speer T1.
Date of e-pub: July 2017
Abstract: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.
We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.
The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.
In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.
Transcriptional networks in rodent models support a role for gut-brain communication in neurogenic hypertension: a review of the evidence.
Author information: Zubcevic J1,2, Baker A1,3, Martyniuk CJ4,3,2.
Date of e-pub: July 2017
Abstract: Hypertension (HTN) is the most prevalent condition observed in primary health care. Hypertension shows complex etiology, and neuroinflammation, overactive sympathetic drive, and the microbiome are each associated with the disease. To obtain mechanistic perspective into neurogenic HTN, we first constructed a framework for transcriptional regulators of the disease using the Comparative Toxicogenomics Database. This approach yielded a core group of 178 transcripts that are prevalent in studies of HTN, including leptin and neuropeptide Y. We then conducted a meta-analysis for transcriptome data generated in brain tissue from HTN studies. Eight expression studies were reanalyzed, in which transcriptomics was conducted in hypertensive animal models [spontaneously hypertensive rats (SHR) and high blood pressure (BPH/2J) Schlager mice] (140 microarrays). Most strikingly, a gut-brain connection was a dominant theme in both rodent models of HTN. The transcriptomic data in the rat CNS converged on processes that included gastrointestinal motility and appetite, among others. In the mouse model, pathways converged on gastrointestinal transit. Thus, our data provide a powerful review of current molecular evidence of the interplay between gut and brain in HTN. Analyses of meta-genome data also suggested that transcriptome networks related to natriuresis, thermoregulation, reproduction (lactation and pregnancy), and vasoconstriction were associated to HTN, supporting physiological observations in independent studies by others. Lastly, we present novel transcriptome networks that may contribute to a neurogenic origin of HTN. Using this framework, new therapeutic targets can be proposed and investigated in treatment strategies.
Use of calcitriol to maintain postpartum blood calcium and improve immune function in dairy cows.
Author information: Vieira-Neto A1, Lima IRP2, Lopes F Jr2, Lopera C2, Zimpel R1, Sinedino LDP1, Jeong KC2, Galvão K3, Thatcher WW1, Nelson CD2, Santos JEP4.
Date of e-pub: July 2017
Abstract: Our objectives were to determine the effects of an injectable formulation of calcitriol on mineral metabolism and immune function in postpartum Holstein cows that received an acidogenic diet prepartum to minimize hypocalcemia. In experiment 1, cows within 6 h of calving received calcitriol (0, 200, or 300 μg) to determine the dose needed to increase plasma concentrations of Ca; 300 μg was sufficient to sustain Ca for at least 3 d. In experiment 2, multiparous cows were assigned randomly to receive only vehicle (control, n = 25) or 300 μg of calcitriol (n = 25) subcutaneously within the first 6 h after calving. Blood was sampled before treatment and 12 h later, then daily until 15 d in milk (DIM), and analyzed for concentrations of ionized Ca (iCa), total Ca (tCa), total Mg (tMg), and total P (tP), metabolites, and hormones. Urine was sampled in the first 7 DIM and analyzed for concentrations of tCa, tMg, and creatinine. Neutrophil function was evaluated in the first week postpartum. Dry matter intake and production performance were evaluated for the first 36 DIM. Calcitriol administration increased concentrations of calcitriol in plasma within 12 h of application from 51 to 427 pg/mL, which returned to baseline within 5 d. Concentrations of iCa and tCa increased 24 h after treatment with calcitriol. Concentrations of iCa (control = 1.08 vs. calcitriol = 1.20 mM), tCa (control = 2.23 vs. calcitriol = 2.33 mM), and tP (control = 1.47 vs. calcitriol = 1.81 mM) remained elevated in cows treated with calcitriol until 3, 5, and 7 DIM, respectively, whereas concentration of tMg (control = 0.76 vs. calcitriol = 0.67 mM) was less in calcitriol cows than control cows until 3 DIM. Concentrations of parathyroid hormone decreased in calcitriol cows compared with control cows (control = 441 vs. calcitriol = 336 pg/mL). Calcitriol tended to increase plasma concentrations of β-hydroxybutyrate and serotonin, but concentrations of glucose, nonesterified fatty acids, and C-telopeptide of type I collagen in plasma did not differ between treatments. Cows treated with calcitriol excreted more urinary tCa (control = 0.5 vs. calcitriol = 2.1 g/d) and tMg (control = 4.5 vs. calcitriol = 5.0 g/d) in the first 7 and 2 DIM, respectively, than control cows. Compared with control, calcitriol improved the proportion of neutrophils with oxidative burst (control = 31.9 vs. calcitriol = 40.6%), mean fluorescence intensity for oxidative burst (control = 90,900 vs. calcitriol = 99,746), and mean fluorescence intensity for phagocytosis (control = 23,887 vs. calcitriol = 28,080). Dry matter intake, yields of milk, and milk components did not differ between treatments. Administration of 300 μg of calcitriol at calving was safe and effective in increasing blood concentration of iCa and plasma concentrations of calcitriol, tCa, and tP for the first 6 d after treatment, and improved measures of innate immune function in early-lactation Holstein cows.
The causes of dispersal and the cost of carry-over effects for an endangered bird in a dynamic wetland landscape.
Author information: Robertson EP1, Fletcher RJ Jr1, Austin JD1.
Date of e-pub: July 2017
Abstract: The decision to disperse or remain philopatric between breeding seasons has important implications for both ecology and evolution, including the potential for carry-over effects, where an individual’s previous history affects its current performance. Carry-over effects are increasingly documented although underlying mechanisms remain unclear. Here we test for potential carry-over effects and their mechanisms by uniting hypotheses for the causes and consequences of habitat selection and dispersal across space and time. We linked hypotheses regarding different types of factors and information (environmental conditions, personal and public information) predicted to impact reproductive success and dispersal for an endangered, wetland-dependent bird, the snail kite (Rostrhamus sociabilis plumbeus). To do so, we coupled structural equation modelling with 20 years of mark-recapture and nesting data across the breeding range of this species to isolate potential direct and indirect effects of these factors. We found that water depth at nest sites explained subsequent emigration rates via an indirect path through the use of personal, not public, information. Importantly, we found that these dispersers tended to initiate nests later the following breeding season. This pattern explained a phenological mismatch of nesting with hydrological conditions, whereby immigrants tended to nest later, late nesters tended to experience lower water depths, higher nest failure occurred at lower water depths and higher nest failure explained subsequent breeding dispersal. These results identified a novel potential mechanism for carry-over effects: a phenological mismatch with environmental conditions (water depth) that occurred potentially due to time costs of dispersal. Our results also highlighted a substantial benefit of philopatry – earlier initiation of reproduction – which allows philopatric individuals to better coincide with environmental conditions that are beneficial for successful reproduction. These results have implications for our mechanistic understanding and prediction of carryover effects, and emphasize that local conservation strategies, such as water management, can explain future demography at distant sites connected through dispersal.
Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor.
Author information: Urban TJ1, Nicoletti P2, Chalasani N3, Serrano J4, Stolz A5, Daly AK6, Aithal GP7, Dillon J8, Navarro V9, Odin J10, Barnhart H11, Ostrov D12, Long N1, Cirulli ET11, Watkins PB1, Fontana RJ13; Drug-Induced Liver Injury Network (DILIN); Pharmacogenetics of Drug-Induced Liver Injury group (DILIGEN); International Serious Adverse Events Consortium (iSAEC).
Date of e-pub: July 2017
Abstract: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.
Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.
Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI.
HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.
Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.
HIV-1 Infection Primes Macrophages Through STAT Signaling to Promote Enhanced Inflammation and Viral Replication.
Author information: Appelberg KS1, Wallet MA1, Taylor JP1, Cash MN1, Sleasman JW2, Goodenow MM1.
Date of e-pub: July 2017
Abstract: Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ (r = .679, p = .003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication.
Population dynamics of hepatitis C virus subtypes in injecting drug users on methadone maintenance treatment in China associated with economic and health reform.
Author information: Zhou S1,2, Cella E3,4,5, Zhou W2, Kong WH2, Liu MQ2, Liu PL2, Ciccozzi M3,6, Salemi M5,7, Chen X2,8.
Date of e-pub: July 2017
Abstract: The extensive genetic heterogeneity of hepatitis C virus (HCV) requires in-depth understanding of the population dynamics of different viral subtypes for more effective control of epidemic outbreaks. We analysed HCV sequences data from 125 participants in Wuhan, China. These participants were newly infected by subtype 1b (n=13), 3a (n=15), 3b (n=50) and 6a (n=39) while on methadone maintenance treatment (MMT). Bayesian phylogenies and demographic histories were inferred for these subtypes. Participants infected with HCV-1b and 3a were clustered in well-supported monophyletic clades, indicating local subepidemics. Subtypes 3b and 6a strains were intermixed with other Chinese isolates, as well as isolates from other Asian countries, reflecting ongoing across geographic boundary transmissions. Subtypes 1b and 3a declined continuously during the past ten years, consistent with the health and economic reform in China, while subtype 3b showed ongoing exponential growth and 6a was characterized by several epidemic waves, possibly related to the recently growing number of travellers between China and other Asian countries. In conclusion, results of this study suggest that HCV subtype 3b and 6a subepidemics in China are currently not under control, and new epidemic waves may emerge given the rapid increase in international travelling following substantial economic growth.
Smart human serum albumin-As2O3 nanodrug with self-amplified folate receptor-targeting ability for chronic myeloid leukemia treatment.
Author information: Peng Y, Zhao Z, Liu T, Li X, Hu X, Wei X, Zhang X, Tan W1.
Date of e-pub: July 2017
Abstract: Arsenic trioxide (ATO, As2O3) is currently used to treat acute promyelocytic leukemia. However, expanding its use to include high-dose treatment of other cancers is severely hampered by serious side effects on healthy organs. To address these limitations, we loaded ATO onto folate (FA)-labeled human serum albumin (HSA) pretreated with glutathione (GSH) based on the low pH- and GSH-sensitive arsenic-sulfur bond, and we termed the resulting smart nanodrug as FA-HSA-ATO. FA-HSA-ATO could specifically recognize folate receptor-β-positive chronic myeloid leukemia (CML) cells, resulting in more intracellular accumulation of ATO. Furthermore, the nanodrug could upregulate FRβ expression in CML cancer cells and xenograft tumor model, facilitating even more recruitment and uptake of FRβ-targeting drugs. In vitro and in vivo experiments indicate that the nanodrug significantly alleviates side effects and improves therapeutic efficacy of ATO on CML and xenograft tumor model.
Structural Elements Recognized by Abacavir-Induced T Cells.
Author information: Yerly D1, Pompeu YA2, Schutte RJ3, Eriksson KK4, Strhyn A5, Bracey AW6, Buus S7, Ostrov DA8.
Date of e-pub: July 2017
Abstract: Adverse drug reactions are one of the leading causes of morbidity and mortality in health care worldwide. Human leukocyte antigen (HLA) alleles have been strongly associated with drug hypersensitivities, and the causative drugs have been shown to stimulate specific T cells at the sites of autoimmune destruction. The structural elements recognized by drug-specific T cell receptors (TCRs) in vivo are poorly defined. Drug-stimulated T cells express TCRs specific for peptide/HLA complexes, but the characteristics of peptides (sequence, or endogenous or exogenous origin) presented in the context of small molecule drugs are not well studied. Using HLA-B*57:01 mediated hypersensitivity to abacavir as a model system, this study examines structural similarities of HLA presented peptides recognized by drug-specific TCRs. Using the crystal structure of HLA-B*57:01 complexed with abacavir and an immunogenic self peptide, VTTDIQVKV SPT5a 976-984, peptide side chains exhibiting flexibility and solvent exposure were identified as potential drug-specific T cell recognition motifs. Viral sequences with structural motifs similar to the immunogenic self peptide were identified. Abacavir-specific T cell clones were used to determine if virus peptides presented in the context of abacavir stimulate T cell responsiveness. An abacavir-specific T cell clone was stimulated by VTQQAQVRL, corresponding to HSV1/2 230-238, in the context of HLA-B*57:01. These data suggest the T cell polyclonal response to abacavir consists of multiple subsets, including T cells that recognize self peptide/HLA-B*57:01 complexes and crossreact with viral peptide/HLA-B*57:01 complexes due to similarity in TCR contact residues.
β-Cell mass versus function in type 1 diabetes mellitus: truth or dare?
Author information: Rodriguez-Calvo T1, Atkinson M2, von Herrath M3.
Date of e-pub: July 2017
Abstract: N/A
Genome Sequence of Oxalobacter formigenes Strain HC-1.
Author information: Hatch M1, Allison MJ2, Yu F3, Farmerie W3.
Date of e-pub: July 2017
Abstract: The lack of Oxalobacter formigenes colonization of the human gut has been correlated with the formation of calcium oxalate kidney stones and also with the number of recurrent kidney stone episodes. Here, we present the genome sequence of HC-1, a human strain isolated from an individual residing in Iowa, USA.
High Illicit Drug Abuse and Suicide in Organ Donors With Type 1 Diabetes.
Author information: Jacobsen LM1,2, Haller MJ1,2, Parish A3, Gurka MJ3, Levine SR1, Wasserfall C2,4, Campbell-Thompson M2,4, Kaddis J5, Pugliese A6, Atkinson MA1,2,4, Schatz DA7,2.
Date of e-pub: July 2017
Abstract: N/A
Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress.
Author information: Kim MH1, Aydemir TB1, Kim J1, Cousins RJ2,3.
Date of e-pub: July 2017
Abstract: Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14-/- (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.
Warfarin Pharmacogenomics in Diverse Populations.
Author information: Kaye JB1, Schultz LE2, Steiner HE1, Kittles RA3,4,5, Cavallari LH6, Karnes JH1,5,7.
Date of e-pub: July 2017
Abstract: Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African-Americans (AAs) and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies and effects of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence with warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. This article is protected by copyright. All rights reserved.
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