bluuebunny/crossref_metadata_2025_split huggingface dataset:
Products of the Parkinson's disease-related glyoxalase DJ-1, D-lactate and glycolate, support mitochondrial membrane potential and neuronal survival
Authors: Toyoda Yusuke , Erkut Cihan , Pan-Montojo Francisco , Boland Sebastian , Stewart Martin P. , Müller Daniel J. , Wurst Wolfgang , Hyman Anthony A. , Kurzchalia Teymuras V. 
Published: July 2014

Abstract
Parkinson's disease is associated with mitochondrial decline in dopaminergic neurons of the substantia nigra. One of the genes linked with the onset of Parkinson's disease, DJ-1/PARK7, belongs to a novel glyoxalase family and influences mitochondrial activity. It has been assumed that glyoxalases fulfill this task by detoxifying aggressive aldehyde by-products of metabolism. Here we show that supplying either D-lactate or glycolate, products of DJ-1, rescues the requirement for the enzyme in maintenance of mitochondrial potential. We further show that glycolic acid and D-lactic acid can elevate lowered mitochondrial membrane potential caused by silencing PINK-1, another Parkinson's related gene, as well as by paraquat, an environmental toxin known to be linked with Parkinson's disease. We propose that DJ-1 and consequently its products are components of a novel pathway that stabilizes mitochondria during cellular stress. We go on to show that survival of cultured mesencephalic dopaminergic neurons, defective in Parkinson's disease, is enhanced by glycolate and D-lactate. Because glycolic and D-lactic acids occur naturally, they are therefore a potential therapeutic route for treatment or prevention of Parkinson's disease.
Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicityin vivo
Authors: Bortolussi Giulia , Baj Gabriele , Vodret Simone , Viviani Giulia , Bittolo Tamara , Muro Andrés F. 
Published: July 2014

AbstractNeonatal jaundice is caused by high levels of unconjugated bilirubin. It is usually a temporary condition due to delayed induction of Ugt1a1, which conjugates bilirubin in the liver. To reduce bilirubin levels, affected babies are exposed to phototherapy (PT), which converts toxic bilirubin into water-soluble photoisomers, readily excreted out. However, in some cases uncontrolled hyperbilirubinemia leads to neurotoxicity. To study the mechanisms of bilirubin-induced neurological damage (BIND) in vivo we generated a mouse model lacking the Ugt1a1 protein and, consequently, mutant mice developed jaundice as early as 36 h after birth. The mutation was transferred into two genetic backgrounds (C57Bl/6 and FVB/NJ). We exposed mutant mice to PT for different periods and analyzed the resulting phenotypes from the molecular, histological and behavioral points of view. Severity of BIND was associated with the genetic background, with 50% survival of C57Bl/6-Ugt1-/- mutant mice at postnatal day 5 (P5) and at P11 for FVB/NJ-Ugt1-/- mice. Life-long exposure to PT prevented cerebellar architecture alterations and rescued neuronal damage in FVB/NJ-Ugt1-/- mice, but not in C57Bl/6 ones. Survival of FVB/NJ-Ugt1-/- mice was directly related to the extent of PT treatment. PT treatment of FVB/NJ-Ugt1-/- mice from P0 to P8 did not prevent bilirubin-induced reduction in dendritic arborization and spine density of Purkinje cells. Moreover, PT treatment from P8 to P20 did not rescue bilirubin-induced neurological damage accumulated up to P8. However, PT treatment administered in the time-window P0-P15 was sufficient to obtain full rescue of cerebellar damage and motor impairment in FVB/NJ-Ugt1-/- mice. The possibility to modulate the severity of the phenotype by PT makes the FVB/NJ-Ugt1-/- mice an excellent and versatile model to study bilirubin neurotoxicity, the role of modifier genes, alternative therapies and cerebellar development during high-bilirubin conditions.
A hierarchy of factors influence discontinuous gas exchange in the grasshopper Paracinema tricolor (Orthoptera: Acrididae)
Authors: Groenewald Berlizé , Chown Steven L. , Terblanche John S. 
Published: July 2014

Abstract
The evolutionary origin and maintenance of discontinuous gas exchange (DGE) in tracheate arthropods are poorly understood and highly controversial. We investigated prioritisation of abiotic factors in the gas exchange control cascade by examining oxygen, water and haemolymph pH regulation in the grasshopper Paracinema tricolor. Using a full-factorial design, grasshoppers were acclimated to hypoxic or hyperoxic (5%O2, 40%O2) gas conditions, or dehydrated or hydrated, whereafter their CO2 release was measured under a range of O2 and relative humidity (RH) conditions (5%, 21%, 40%O2 and 5%, 60%, 90%RH). DGE was significantly less common in grasshoppers acclimated to dehydrating conditions compared to the other acclimations (hypoxia=98%; hyperoxia=100%; hydrated=100%; dehydrated=67%). The dehydrated acclimation resulted in a significant decrease in haemolymph pH from 7.0 ± 0.3 to 6.6 ± 0.1 (mean ± standard deviation, p=0.018) and also significantly increased the O-phase duration under 5%O2 treatment conditions (5%O2=44.1 ± 29.3 min; 40%O2=15.8 ± 8.0 min; 5%RH=17.8 ± 1.3 min; 60%RH=24.0 ± 9.7 min; 90%RH=20.6 ± 8.9 min (mean ± standard deviation)). The observed acidosis could potentially explain the extension of the O-phase under low RH conditions, when it would perhaps seem more useful to reduce the O-phase to lower respiratory water loss. The results confirm that DGE occurrence and modulation is affected by multiple abiotic factors. A hierarchical framework for abiotic factors influencing DGE is proposed in which the following stressors are prioritised in decreasing order of importance: oxygen supply; CO2 excretion and pH modulation; oxidative damage protection and water savings.
Paracellular nutrient absorption is higher in bats than rodents: integrating from intact animals to the molecular level
Authors: Price Edwin R. , Rott Katherine H. , Caviedes-Vidal Enrique , Karasov William H. 
Published: July 2014

AbstractFlying vertebrates have been hypothesized to rely heavily on paracellular absorption of nutrients to compensate for having smaller intestines than non-flyers. We tested this hypothesis in an insectivorous bat (Myotis lucifugus) and two insect-eating rodents (Onychomys leucogaster and Peromyscus leucopus). In intact animals, the fractional absorption of orally dosed L-arabinose (Mr 150) was 82% in M. lucifugus, which was more than twice that of the rodents. Absorption of creatinine (Mr 113) was greater than 50% for all species and did not differ between M. lucifugus and the rodents. We also conducted intestinal luminal perfusions on anesthetized animals. Absorption of L-arabinose per nominal surface area in M. lucifugus was nearly double that of the rodents, while absorption of creatinine was not different among species. Using an everted sleeve preparation, we demonstrated that high concentrations of L-arabinose and creatinine did not inhibit their own uptake, validating their use as passive, paracellular probes. Histological measurements indicated that M. lucifugus has more cells, and presumably more tight junctions, per nominal surface area than P. leucopus. This seems unlikely to explain entirely the higher absorption of L-arabinose in M. lucifugus during perfusions, because L-arabinose absorption normalized to the number of enterocytes was still double that of P. leucopus. As an alternative, we investigated tight junction gene expression. M. lucifugus had higher expression of claudin-1 and -15, and lower expression of claudin-2 relative to P. leucopus. Expression of claudin-7 and occludin did not differ among species. Taken together, our results support the hypothesis that bats have evolved higher paracellular nutrient absorption than non-flying animals, and that this phenomenon might be driven by both histological characteristics and differences in tight-junction gene expression.
Effects of field-realistic doses of glyphosate on honeybee appetitive behaviour
Authors: Herbert Lucila H. , Vazquez Diego E. , Arenas Andres , Farina Walter M. 
Published: July 2014

AbstractGlyphosate (GLY) is a broad spectrum herbicide used for weed control. Presently, sub-lethal impact of GLY on non-target organisms such as insect pollinators has not been evaluated yet. Apis mellifera is the main pollinator in agricultural environments and a well-known model for behavioural research. Moreover, honeybees are accurate biosensors of environmental pollutants and their appetitive behavioural response is a suitable tool to test sub-lethal effects of agrochemicals. We studied the effects of field-realistic doses of GLY on honeybees exposed chronically or acutely to it. We focused on sucrose sensitivity, elemental and non-elemental associative olfactory conditioning of the proboscis extension response (PER) and on foraging related behaviour. We found a reduced sensitivity to sucrose and learning performance for the groups chronically exposed to GLY concentrations within the range of recommended doses. When olfactory PER conditioning was performed with sucrose reward with the same GLY concentrations (acute exposure), elemental learning and short-term memory retention decreased significantly compared to controls. Non-elemental associative learning was also impaired by an acute exposure to GLY traces. Altogether, these results imply that GLY at concentrations found in agro-ecosystems due to standard spraying can reduce sensitivity to nectar reward and impair associative learning in honeybees. However, no effect on foraging related behaviour was found. Therefore, we speculate that successful forager bees could become a source of constant inflow of nectar with GLY traces that could then be distributed among nest mates, stored in the hive and have long-term negative consequences on colony performance.
Cardiac Troponin I Associated with the Development of Unrecognized Myocardial Infarctions Detected with MRI
Authors: Barbier Charlotte Ebeling , Themudo Raquel , Bjerner Tomas , Johansson Lars , Lindahl Bertil , Venge Per , Lind Lars , Ahlström Håkan 
Published: July 2014

Abstract

BACKGROUND
Late enhancement MRI (LE-MRI) and cardiac troponin I (cTnI) are sensitive methods to detect subclinical myocardial injury. We sought to investigate the relation between plasma concentrations of cTnI measured with a high-sensitivity assay (hs-cTnI) and the development of unrecognized myocardial infarctions (UMIs) detected with LE-MRI.

METHODS
After approval from the ethics committee and written informed consent were obtained, LE-MRI was performed on 248 randomly selected community-living 70-year-old volunteers and hs-cTnI was determined with a highly sensitive premarket assay. Five years later these individuals were invited to a second LE-MRI, and 176 of them (82 women, 94 men), who did not have a hospital diagnosis of MI, constitute the present study population. LE-MR images were analyzed by 2 radiologists independently and in a consensus reading, blinded to any information on previous disease or assessments.

RESULTS
New or larger UMIs were detected in 37 participants during follow-up. Plasma concentrations of hs-cTnI at 70 years of age, which were mainly within what is considered to be the reference interval, were related to new or larger UMIs at 75 years of age with an odds ratio of 1.98 per 1 unit increase in ln-transformed cTnI (95% CI, 1.17–3.35; P = 0.010). Plasma concentrations of hs-cTnI at 70 years of age were associated with the volumes of the UMIs detected at 75 years of age (P = 0.028).

CONCLUSIONS
hs-cTnI in 70-year-old community-living women and men was associated with the development of MRI-detected UMIs within 5 years.
Reduced pachytene piRNAs and translation underlie spermiogenic arrest in Maelstrom mutant mice
Authors: Castañeda Julio , Genzor Pavol , van der Heijden Godfried W , Sarkeshik Ali , Yates John R , Ingolia Nicholas T , Bortvin Alex 
Published: July 2014

AbstractPachytene piRNAs are a class of Piwi‐interacting small RNAs abundant in spermatids of the adult mouse testis. They are processed from piRNA primary transcripts by a poorly understood mechanism and, unlike fetal transposon‐derived piRNAs, lack complementary targets in the spermatid transcriptome. We report that immunopurified complexes of a conserved piRNA pathway protein Maelstrom (MAEL) are enriched in MIWI (Piwi partner of pachytene piRNAs), Tudor‐domain proteins and processing intermediates of pachytene piRNA primary transcripts. We provide evidence of functional significance of these complexes in Mael129 knockout mice that exhibit spermiogenic arrest with acrosome and flagellum malformation. Mael129‐null mutant testes possess low levels of piRNAs derived from MAEL‐associated piRNA precursors and exhibit reduced translation of numerous spermiogenic mRNAs including those encoding acrosome and flagellum proteins. These translation defects in haploid round spermatids are likely indirect, as neither MAEL nor piRNA precursors associate with polyribosomes, and they may arise from an imbalance between pachytene piRNAs and MIWI.
TLR sorting by Rab11 endosomes maintains intestinal epithelial‐microbial homeostasis
Authors: Yu Shiyan , Nie Yingchao , Knowles Byron , Sakamori Ryotaro , Stypulkowski Ewa , Patel Chirag , Das Soumyashree , Douard Veronique , Ferraris Ronaldo P , Bonder Edward M , Goldenring James R , Ip Yicktung Tony , Gao Nan 
Published: July 2014

AbstractCompartmentalization of Toll‐like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a, a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell‐intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild‐type controls, germ‐free Rab11a‐deficient mouse intestines failed to tolerate the intraluminal stimulation of microbial agonists. Thus, Rab11a endosome controls intestinal host‐microbial homeostasis at least partially via sorting TLRs.
A positive signal prevents secretory membrane cargo from recycling between the Golgi and the ER
Authors: Fossati Matteo , Colombo Sara F , Borgese Nica 
Published: July 2014

AbstractThe Golgi complex and ER are dynamically connected by anterograde and retrograde trafficking pathways. To what extent and by what mechanism outward‐bound cargo proteins escape retrograde trafficking has been poorly investigated. Here, we analysed the behaviour of several membrane proteins at the ER/Golgi interface in live cells. When Golgi‐to‐plasma membrane transport was blocked, vesicular stomatitis virus glycoprotein (VSVG), which bears an ER export signal, accumulated in the Golgi, whereas an export signal‐deleted version of VSVG attained a steady state determined by the balance of retrograde and anterograde traffic. A similar behaviour was displayed by EGF receptor and by a model tail‐anchored protein, whose retrograde traffic was slowed by addition of VSVG's export signal. Retrograde trafficking was energy‐ and Rab6‐dependent, and Rab6 inhibition accelerated signal‐deleted VSVG's transport to the cell surface. Our results extend the dynamic bi‐directional relationship between the Golgi and ER to include surface‐directed proteins, uncover an unanticipated role for export signals at the Golgi complex, and identify recycling as a novel factor that regulates cargo transport out of the early secretory pathway.
Aberrant methylation of tRNAs links cellular stress to neuro‐developmental disorders
Authors: Blanco Sandra , Dietmann Sabine , Flores Joana V , Hussain Shobbir , Kutter Claudia , Humphreys Peter , Lukk Margus , Lombard Patrick , Treps Lucas , Popis Martyna , Kellner Stefanie , Hölter Sabine M , Garrett Lillian , Wurst Wolfgang , Becker Lore , Klopstock Thomas , Fuchs Helmut , Gailus‐Durner Valerie , Hrabĕ de Angelis Martin , Káradóttir Ragnhildur T , Helm Mark , Ule Jernej , Gleeson Joseph G , Odom Duncan T , Frye Michaela 
Published: July 2014

AbstractMutations in the cytosine‐5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post‐transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine‐5 RNA methylomes in patient fibroblasts and NSun2‐deficient mice, we find that loss of cytosine‐5 RNA methylation increases the angiogenin‐mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5′ tRNA‐derived small RNA fragments. Accumulation of 5′ tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site‐specific NSun2‐mediated methylation and that the presence of 5′ tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2‐deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2‐mediated tRNA methylation contributes to human diseases via stress‐induced RNA cleavage.
Stop competing, start talking!
Authors: Fava Luca L , Villunger Andreas 
Published: July 2014

According to current belief, the molecular networks orchestrating cell death or exit from mitosis upon extended mitotic arrest do not interact, stubbornly executing two parallel biological programs and competing to define a stochastic decision between death and a chance for survival with uncertain destiny. However, recent findings by Diaz‐Martinez et al () in this issue of The EMBO Journal now call for a reassessment of the “competing network” hypothesis.
Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease
Authors: Goveia Jermaine , Stapor Peter , Carmeliet Peter 
Published: July 2014

AbstractThe endothelium is the orchestral conductor of blood vessel function. Pathological blood vessel formation (a process termed pathological angiogenesis) or the inability of endothelial cells (ECs) to perform their physiological function (a condition known as EC dysfunction) are defining features of various diseases. Therapeutic intervention to inhibit aberrant angiogenesis or ameliorate EC dysfunction could be beneficial in diseases such as cancer and cardiovascular disease, respectively, but current strategies have limited efficacy. Based on recent findings that pathological angiogenesis and EC dysfunction are accompanied by EC‐specific metabolic alterations, targeting EC metabolism is emerging as a novel therapeutic strategy. Here, we review recent progress in our understanding of how EC metabolism is altered in disease and discuss potential metabolic targets and strategies to reverse EC dysfunction and inhibit pathological angiogenesis.
Taxanes as a Risk Factor for Acute Adverse Reactions to Iodinated Contrast Media in Cancer Patients
Authors: Farolfi Alberto , Della Luna Corradina , Ragazzini Angela , Carretta Elisa , Gentili Nicola , Casadei Carla , Aquilina Michele , Barone Domenico , Minguzzi Martina , Amadori Dino , Nanni Oriana , Gavelli Giampaolo 
Published: July 2014

Abstract

Background.
The impact of cytotoxic agents on the risk of acute allergy-like adverse reactions (ARs) to intravenous iodinated contrast media (ICM) injections is unknown.

Methods.
We retrospectively reviewed 13,565 computed tomography (CT) scans performed in a consecutive cohort of cancer patients from January 1, 2010 to December 31, 2012. Episodes of acute ICM-related ARs were reported to the pharmacovigilance officer. The following matched comparisons were made: tax code, gender, primary tumor, antineoplastic therapy, and date of last cycle. Concomitant antineoplastic treatment was classified into five groups: platinum, taxane, platinum plus taxane, other, and no treatment group (no therapy had been administered in the previous 24 months). Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) to evaluate the risk of acute ICM-related ARs.

Results.
Of 10,472 contrast-enhanced CT scans, 97 (0.93%; 95% CI: 0.74–1.11) ICM-related ARs were reported, 11 of which (0.1%) were severe, including one fatality. The overall incidence was significantly higher in patients aged &lt;65 years (p = .0062) and in the platinum plus taxane and taxane groups (p = .007), whereas no correlation was found with gender, number of previous CT scans, site of disease, or treatment setting. Multivariate analysis confirmed an increased risk for patients aged &lt;65 years (OR: 1.73; 95% CI: 1.14–2.63) and for the taxane group (in comparison with the no treatment group; OR: 2.06; 95% CI: 1.02–4.16).

Conclusion.
Among cancer patients, concomitant treatment with taxanes and younger age would seem to be risk factors for ICM-related ARs.
European Perspective on Multiple Myeloma Treatment Strategies in 2014
Authors: Ludwig Heinz , Sonneveld Pieter , Davies Faith , Bladé Joan , Boccadoro Mario , Cavo Michele , Morgan Gareth , de la Rubia Javier , Delforge Michel , Dimopoulos Meletios , Einsele Hermann , Facon Thierry , Goldschmidt Hartmut , Moreau Philippe , Nahi Hareth , Plesner Torben , San-Miguel Jesús , Hajek Roman , Sondergeld Pia , Palumbo Antonio 
Published: July 2014

Abstract
The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on “fitness,” with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results.