bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
Authors: Tian Chang-Qing , Chen Lin , Chen Hua-Dong , Huan Xia-Juan , Hu Jian-Ping , Shen Jing-Kang , Xiong Bing , Wang Ying-Qing , Miao Ze-Hong 
Published: July 2019

AbstractThe bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l-kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1. Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of l-kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced l-kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.
Dopey1-Mon2 complex binds to dual-lipids and recruits kinesin-1 for membrane trafficking
Authors: Mahajan Divyanshu , Tie Hieng Chiong , Chen Bing , Lu Lei 
Published: July 2019

AbstractProteins are transported among eukaryotic organelles along the cytoskeleton in membrane carriers. The mechanism regarding the motility of carriers and the positioning of organelles is a fundamental question in cell biology that remains incompletely understood. Here, we find that Dopey1 and Mon2 assemble into a complex and localize to the Golgi, endolysosome and endoplasmic reticulum exit site. The Golgi localization of Dopey1 and Mon2 requires their binding to phosphatidylinositol-4-phosphate and phosphatidic acid, respectively, two lipids known for the biogenesis of membrane carriers and the specification of organelle identities. The N-terminus of Dopey1 further interacts with kinesin-1, a plus-end or centrifugal-direction microtubule motor. Dopey1-Mon2 complex functions as a dual-lipid-regulated cargo-adaptor to recruit kinesin-1 to secretory and endocytic organelles or membrane carriers for centrifugally biased bidirectional transport. Dopey1-Mon2 complex therefore provides an important missing link to coordinate the budding of a membrane carrier and subsequent bidirectional transport along the microtubule.
Molecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy
Authors: Niemann Julia , Woller Norman , Brooks Jennifer , Fleischmann-Mundt Bettina , Martin Nikolas T. , Kloos Arnold , Knocke Sarah , Ernst Amanda M. , Manns Michael P. , Kubicka Stefan , Wirth Thomas C. , Gerardy-Schahn Rita , Kühnel Florian 
Published: July 2019

AbstractVirus-neutralizing antibodies are a severe obstacle in oncolytic virotherapy. Here, we present a strategy to convert this unfavorable immune response into an anticancer immunotherapy via molecular retargeting. Application of a bifunctional adapter harboring a tumor-specific ligand and the adenovirus hexon domain DE1 for engaging antiadenoviral antibodies, attenuates tumor growth and prolongs survival in adenovirus-immunized mice. The therapeutic benefit achieved by tumor retargeting of antiviral antibodies is largely due to NK cell-mediated triggering of tumor-directed CD8 T-cells. We further demonstrate that antibody-retargeting (Ab-retargeting) is a feasible method to sensitize tumors to PD-1 immune checkpoint blockade. In therapeutic settings, Ab-retargeting greatly improves the outcome of intratumor application of an oncolytic adenovirus and facilitates long-term survival in treated animals when combined with PD-1 checkpoint inhibition. Tumor-directed retargeting of preexisting or virotherapy-induced antiviral antibodies therefore represents a promising strategy to fully exploit the immunotherapeutic potential of oncolytic virotherapy and checkpoint inhibition.
Rapid inundation of southern Florida coastline despite low relative sea-level rise rates during the late-Holocene
Authors: Jones Miriam C. , Wingard G. Lynn , Stackhouse Bethany , Keller Katherine , Willard Debra , Marot Marci , Landacre Bryan , E. Bernhardt Christopher 
Published: July 2019

AbstractSediment cores from Florida Bay, Everglades National Park were examined to determine ecosystem response to relative sea-level rise (RSLR) over the Holocene. High-resolution multiproxy analysis from four sites show freshwater wetlands transitioned to mangrove environments 4–3.6 ka, followed by estuarine environments 3.4–2.8 ka, during a period of enhanced climate variability. We calculate a RSLR rate of 0.67 ± 0.1 mm yr−1 between ~4.2–2.8 ka, 4–6 times lower than current rates. Despite low RSLR rates, the rapid mangrove to estuarine transgression was facilitated by a period of prolonged droughts and frequent storms. These findings suggest that with higher and accelerating RSLR today, enhanced climate variability could further hasten the loss of mangrove-lined coastlines, compounded by the reductions in natural flow to the coast caused by water management. Climate variability is nonlinear, and when superimposed on increases in RSLR, can complicate estimated trajectories of coastal inundation for resource management and urban planning.
Active thrombin produced by the intestinal epithelium controls mucosal biofilms
Authors: Motta Jean-Paul , Denadai-Souza Alexandre , Sagnat David , Guiraud Laura , Edir Anissa , Bonnart Chrystelle , Sebbag Mireille , Rousset Perrine , Lapeyre Ariane , Seguy Carine , Mathurine-Thomas Noa , Galipeau Heather J. , Bonnet Delphine , Alric Laurent , Buret Andre G. , Wallace John L. , Dufour Antoine , Verdu Elena F. , Hollenberg Morley D. , Oswald Eric , Serino Matteo , Deraison Celine , Vergnolle Nathalie 
Published: July 2019

AbstractProteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin.
Antimalarial activity of primaquine operates via a two-step biochemical relay
Authors: Camarda Grazia , Jirawatcharadech Piyaporn , Priestley Richard S. , Saif Ahmed , March Sandra , Wong Michael H. L. , Leung Suet , Miller Alex B. , Baker David A. , Alano Pietro , Paine Mark J. I. , Bhatia Sangeeta N. , O’Neill Paul M. , Ward Stephen A. , Biagini Giancarlo A. 
Published: July 2019

AbstractPrimaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.
Real-time optical and electronic sensing with a β-amino enone linked, triazine-containing 2D covalent organic framework
Authors: Kulkarni Ranjit , Noda Yu , Kumar Barange Deepak , Kochergin Yaroslav S. , Lyu Pengbo , Balcarova Barbora , Nachtigall Petr , Bojdys Michael J. 
Published: July 2019

AbstractFully-aromatic, two-dimensional covalent organic frameworks (2D COFs) are hailed as candidates for electronic and optical devices, yet to-date few applications emerged that make genuine use of their rational, predictive design principles and permanent pore structure. Here, we present a 2D COF made up of chemoresistant β-amino enone bridges and Lewis-basic triazine moieties that exhibits a dramatic real-time response in the visible spectrum and an increase in bulk conductivity by two orders of magnitude to a chemical trigger - corrosive HCl vapours. The optical and electronic response is fully reversible using a chemical switch (NH3 vapours) or physical triggers (temperature or vacuum). These findings demonstrate a useful application of fully-aromatic 2D COFs as real-time responsive chemosensors and switches.
Autoimmunthyreoiditis
Authors: Bieger Wilfried P. 
Published: July 2019

ZusammenfassungIn Deutschland sind etwa 5 % der Bevölkerung an einer Autoimmunthyreoiditis (AITD) erkrankt, wobei die Hashimoto-Thyreoiditis häufiger ist als Morbus Basedow. Bei beiden Autoimmunerkrankungen sind Frauen deutlich häufiger betroffen als Männer, familiäre Häufungen sind bekannt und nicht selten leiden die Patienten gleichzeitig an weiteren Autoimmunopathien. Die Ätiologie der AIDT gilt als multifaktoriell, der Beitrag genetischer Faktoren wird auf 75 % geschätzt. Umweltfaktoren haben einen Anteil von 20 % an der Inzidenz. Als Trigger wurden u. a. Rauchen, Infektionen, Stress und Selenmangel identifiziert. Möglichkeiten der Diagnostik und Therapie werden zusammenfassend dargestellt.
Überleben bei ALS?
Authors: Mutter Joachim 
Published: July 2019

ZusammenfassungZahlreiche wissenschaftliche Arbeiten belegen einen Zusammenhang zwischen Schwermetallbelastungen und neurodegenerativen Erkrankungen wie ALS. Immer wieder in der Diskussion sind Zahnfüllungen aus Amalgam, die in Deutschland trotz vielzähliger gegenteiliger Belege noch immer als unschädlich eingestuft werden. Die WHO hat diese bereits 1991 als Hauptquelle für Quecksilberbelastungen eingestuft.Für ALS gibt es bislang keine kurative Therapie, die Prognose ist in den meisten Fällen sehr ungünstig. Eine Ausleitungstherapie mit Chelatbildnern hat sich als nicht schädlich, sondern vielmehr lebensrettend und ursächlich gezeigt, was internationale wissenschaftliche Arbeiten bestätigen.
Distribution and temporal trends of temperature extremes over Antarctica
Authors: Wei Ting , Yan Qing , Ding Minghu 
Published: July 2019

Abstract
The spatiotemporal characteristics of temperature extremes over Antarctica remain largely unknown. Here, we use quality-controlled daily datasets from Antarctic weather stations to show that the annual maximum and minimum temperatures exhibit a decreasing pattern over Antarctica from the coast to inland regions. This feature holds for the warmest daily maximum and coldest daily minimum temperatures, which define the intensity of extremes, but not for the number of warm (cold) days measuring the frequency of extremes, which show limited dependence on latitude or elevation. During 1970–2000, the temperature extremes in the South Orkney islands and on the margins of East Antarctica show opposite trends, especially with a significant increasing and decreasing trend in warm events, respectively. During 1999–2013, the intensity and frequency of extreme temperatures decrease significantly over West Antarctica, but the trends vary greatly across sub-regions of Antarctica. Despite the limited number of stations and the potential time dependence of trends, these results not only help to decipher the climate regimes of Antarctica and fill current gaps in the map of global climate extremes, but also may guide the future design of Antarctic observational networks and be used to assess the capability of reanalysis datasets and climate models.
Steroidogenic acute regulatory protein and luteinizing hormone are required for normal ovarian steroidogenesis and oocyte maturation in zebrafish†
Authors: Shang Guohui , Peng Xuyan , Ji Cheng , Zhai Gang , Ruan Yonglin , Lou Qiyong , Jin Xia , He Jiangyan , Wang Han , Yin Zhan 
Published: July 2019

Abstract
In recent studies, luteinizing hormone (LH) was reported to play important roles in oocyte maturation. However, the mechanism by which LH signaling, especially regarding the steroidogenesis process, affects oocyte maturation has not been clarified. In this study, zebrafish models with a functional deficiency in luteinizing hormone beta (Lhb) or steroidogenic acute regulatory protein (Star), an enzyme that promotes the transport of cholesterol into the inner mitochondrial membrane for maturation-induced hormone (MIH) production, were generated using transcription activator-like effector nucleases (TALENs). Similar phenotypes of the maturation-arrested oocytes in both female mutants have been observed. The levels of MIH in the oocytes of the female mutants were clearly decreased in both the lhb and star knockout zebrafish. The expression of star was dramatically down-regulated in the lhb mutant follicles and was clearly promoted by forskolin and hCG in vitro. Furthermore, treatment with the MIH precursors, pregnenolone or progesterone, as well as with MIH itself rescued the maturation-arrested oocyte phenotypes in both lhb and star mutants. The plasma levels of other steroids, including testosterone, estradiol, and cortisol, were not affected in the lhb mutants, while the levels of gonad hormones testosterone and estradiol were significantly increased in the star mutants. The cortisol levels were decreased in the star mutants. Collectively, our results confirm that LH plays important roles in the initiation of MIH synthesis from cholesterol and maintains oocyte maturation in zebrafish, as well as provide evidence that Star might act downstream of LH signaling in steroidogenesis.
Association Between Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection in Early Life and Recurrent Wheeze and Asthma in Later Childhood
Authors: Shi Ting , Ooi Yujing , Zaw Ei Mon , Utjesanovic Natasa , Campbell Harry , Cunningham Steve , Bont Louis , Nair Harish ,   RESCEU Investigators, Nair Harish , Campbell Harry , Shi Ting , Zhang Shanshan , Li You , Openshaw Peter , Wedzicha Jadwicha , Falsey Ann , Miller Mark , Beutels Philippe , Bont Louis , Pollard Andrew , Molero Eva , Martinon-Torres Federico , Heikkinen Terho , Meijer Adam , Fischer Thea Kølsen , van den Berge Maarten , Giaquinto Carlo , Mikolajczyk Rafael , Hackett Judy , Cai Bing , Knirsch Charles , Leach Amanda , Stoszek Sonia K , Gallichan Scott , Kieffer Alexia , Demont Clarisse , Cheret Arnaud , Gavart Sandra , Aerssens Jeroen , Wyffels Veronique , Cleenewerck Matthias , Fuentes Robert , Rosen Brian , Nair Harish , Campbell Harry , Shi Ting , Zhang Shanshan , Li You , Openshaw Peter , Wedzicha Jadwicha , Falsey Ann , Miller Mark , Beutels Philippe , Bont Louis , Pollard Andrew , Molero Eva , Martinon-Torres Federico , Heikkinen Terho , Meijer Adam , Fischer Thea Kølsen , van den Berge Maarten , Giaquinto Carlo , Mikolajczyk Rafael , Hackett Judy , Cai Bing , Knirsch Charles , Leach Amanda , Stoszek Sonia K , Gallichan Scott , Kieffer Alexia , Demont Clarisse , Cheret Arnaud , Gavart Sandra , Aerssens Jeroen , Wyffels Veronique , Cleenewerck Matthias , Fuentes Robert , Rosen Brian 
Published: July 2019

AbstractBackgroundRecurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years.MethodsWe estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population.ResultsOverall, we included 41 studies. A statistically significant association was observed between early life RSV infection and subsequent childhood recurrent wheeze, in comparison to those who were healthy or those without respiratory symptoms: OR 3.05 (95% confidence interval [CI], 2.50–3.71) for 0 to &lt;36 months follow-up age; OR 2.60 (95% CI, 1.67–4.04) for 36–72 months; and OR 2.14 (95% CI, 1.33–3.45) for 73–144 months. For the subsequent development of asthma, a statistically significant association was observed only in relation to those aged 73–144 months at follow-up: OR 2.95 (95% CI, 1.96–4.46).ConclusionsFurther studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.
An Updated Conceptual Model on the Pathogenesis of Bacterial Vaginosis
Authors: Muzny Christina A , Taylor Christopher M , Swords W Edward , Tamhane Ashutosh , Chattopadhyay Debasish , Cerca Nuno , Schwebke Jane R 
Published: July 2019

AbstractBacterial vaginosis (BV) is the most common cause of vaginal discharge. It is associated with an increased risk of preterm delivery, pelvic inflammatory disease, and an increased risk of acquisition of sexually transmitted infections including human immunodeficiency virus (HIV). The epidemiology of BV supports sexual transmission. However, its etiology remains unknown. At the center of the debate is whether BV is caused by a primary pathogen or a polymicrobial consortium of microorganisms that are sexually transmitted. We previously published a conceptual model hypothesizing that BV is initiated by sexual transmission of Gardnerella vaginalis. Critics of this model have iterated that G. vaginalis is found in virginal women and in sexually active women with a normal vaginal microbiota. In addition, colonization does not always lead to BV. However, recent advances in BV pathogenesis research have determined the existence of 13 different species within the genus Gardnerella. It may be that healthy women are colonized by nonpathogenic Gardnerella species, whereas virulent strains are involved in BV development. Based on our results from a recent prospective study, in addition to an extensive literature review, we present an updated conceptual model for the pathogenesis of BV that centers on the roles of virulent strains of G. vaginalis, as well as Prevotella bivia and Atopobium vaginae.
cis-12-Oxo-phytodienoic acid represses Arabidopsis seed germination in shade conditions
Authors: Barros-Galvão Thiago , Dave Anuja , Cole Adama , Harvey David , Langer Swen , Larson Tony R , Vaistij Fabián E , Graham Ian A 
Published: July 2019

Abstract
Light-dependent seed germination is induced by gibberellins (GA) and inhibited by abscisic acid (ABA). The widely accepted view of the GA/ABA ratio controlling germination does not, however, explain the fact that seeds deficient in ABA still germinate poorly under shade conditions that repress germination. In Arabidopsis, MOTHER-OF-FT-AND-TFL1 (MFT) acts as a key negative regulator of germination, modulating GA and ABA responses under shade conditions. Under full light the oxylipin cis-12-oxo-phytodienoic acid (OPDA), a precursor of the stress-related phytohormone jasmonic acid, interacts with ABA and MFT to repress germination. Here, we show that under shade conditions both OPDA and ABA repress germination to varying extents. We demonstrate that the level of shade-induced MFT expression influences the ability of OPDA and/or ABA to fully repress germination. We also found that MFT expression decreases with seed age and this again correlates with the response of seeds to OPDA and ABA. We conclude that OPDA plays an essential role alongside ABA in repressing germination in response to shade and the combined effect of these phytohormones is integrated to a significant extent through MFT.
Magnifications of paired micro-images emerging from a micro-lensing critical curve
Authors: Weisenbach Luke , Schechter Paul , Wambsganss Joachim 
Published: July 2019

Abstract
Studies of the inner regions of micro-lensed active galactic nucleus during caustic crossing events have often relied upon the approximation that the magnification near a fold caustic is inversely proportional to the square root of the source-caustic distance. We examine here the behaviour of the individual micro-images (one a micro-minimum of the light traveltime, the other a micro-saddle) that emerge as a point source crosses a micro-fold caustic. We provide a variety of statistics on both the behaviour of the two newly created micro-images and some parameters that appear in higher order approximations for the magnification. We compare the predictions of these higher order approximations to the actual image magnifications of our simulations.
Dietary vitamin D interacts with high phosphate-induced cardiac remodeling in rats with normal renal function
Authors: Hu Ming Chang , Scanni Roberto , Ye Jianfeng , Zhang Jianning , Shi Mingjun , Maique Jenny , Flores Brianna , Moe Orson W , Krapf Reto 
Published: July 2019

Abstract

Background
Vitamin D (VD) and phosphate (Pi) load are considered as contributors to cardiovascular disease in chronic kidney disease and the general population, but interactive effects of VD and Pi intake on the heart are not clearly illustrated.

Methods
We fed normal male rats with three levels of dietary VD (100, 1100 or 5000 IU/kg chow) and Pi (0.2, 0.6 or 1.6%) (3X3 design) for 8 weeks and examined renal and cardiac function and histology.

Results
High dietary Pi decreased plasma and renal Klotho and plasma 25-hydroxyvitamin D, and increased plasma Pi, fibroblast growth factor 23 and parathyroid hormone without affecting renal function, while low Pi increased plasma and renal Klotho. Both low and high VD diets enhanced high Pi-reduced Klotho expression. Low dietary VD reduced-plasma Klotho was rescued by a low Pi diet. High dietary Pi reduced-cardiac ejection fraction was not modified by a low or high VD diet, but the dietary VD effects on cardiac pathologic changes were more complex. High dietary Pi-induced cardiac hypertrophy was attenuated by a low VD and exacerbated by a high VD diet. In contrast, high dietary Pi -induced cardiac fibrosis was magnified by a low VD and attenuated by a high VD diet.

Conclusions
High Pi diet induces hypertrophy and fibrosis in left ventricles, a low VD diet accelerates high Pi-induced fibrosis, and a high VD diet exacerbated high Pi -induced hypertrophy. Therefore, cardiac phosphotoxicity is exacerbated by either high or low dietary VD in rats with normal kidney function.