bluuebunny/crossref_metadata_2025 huggingface dataset:
Nascent RNA folding mitigates transcription-associated mutagenesis
Authors: Chen Xiaoshu , Yang Jian-Rong , Zhang Jianzhi
Published: October 2015

Transcription is mutagenic, in part because the R-loop formed by the binding of the nascent RNA with its DNA template exposes the nontemplate DNA strand to mutagens and primes unscheduled error-prone DNA synthesis. We hypothesize that strong folding of nascent RNA weakens R-loops and hence decreases mutagenesis. By a yeast forward mutation assay, we show that strengthening RNA folding and reducing R-loop formation by synonymous changes in a reporter gene can lower mutation rate by >80%. This effect is diminished after the overexpression of the gene encoding RNase H1 that degrades the RNA in a DNA–RNA hybrid, indicating that the effect is R-loop-dependent. Analysis of genomic data of yeast mutation accumulation lines and human neutral polymorphisms confirms the generality of these findings. This mechanism for local protection of genome integrity is of special importance to highly expressed genes because of their frequent transcription and strong RNA folding, the latter also improves translational fidelity. As a result, strengthening RNA folding simultaneously curtails genotypic and phenotypic mutations.
Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains
Authors: Ulianov Sergey V. , Khrameeva Ekaterina E. , Gavrilov Alexey A. , Flyamer Ilya M. , Kos Pavel , Mikhaleva Elena A. , Penin Aleksey A. , Logacheva Maria D. , Imakaev Maxim V. , Chertovich Alexander , Gelfand Mikhail S. , Shevelyov Yuri Y. , Razin Sergey V.
Published: October 2015

Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding inDrosophila melanogaster, we performed Hi-C and poly(A)+RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) inDrosophilaare only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However,Drosophilainter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.
Post‐Democracy, Press, Politics and Power
Authors: Fenton Natalie
Published: October 2015

Transnational media corporations now wield enormous power and influence. Never has this been displayed so starkly and so shockingly as in the revelations that emerged during the Leveson Inquiry into the culture and ethics of the press in the UK. This paper considers the implications of the relationship between media elites and political elites for democratic culture and media reform. The paper argues that the culture of press–politician mutual interest in which media executives and party leaders collude will continue as long as the solutions proffered focus on the ethical constraints of professional journalists rather than wider structural issues relating to plurality of ownership and control and funding of news in the public interest.
Is Liberal Democracy Sliding into ‘Democratic Despotism’?
Authors: Pabst Adrian
Published: October 2015

Post‐democracy and cognate concepts suggest that the postwar period of democratisation has given way to a concentration of power in the hands of small groups that are unrepresentative and unaccountable, as exemplified by the rise of multinational corporations and their influence on democratic politics. This article goes further to argue that this does not fully capture the triple threat facing liberal democracy: first, the rise of a new oligarchy that strengthens executive power at the expense of parliament and people; second, the resurgence of populism and demagogy linked to a backlash against technocratic rule and procedural politics; third, the emergence of anarchy associated with the atomisation of society and a weakening of social ties and civic bonds. In consequence, liberal democracy risks sliding into a form of ‘democratic despotism’ that maintains the illusion of free choice while instilling a sense of ‘voluntary servitude’ as conceptualised by Tocqueville.
Occupancy estimation for rare species using a spatially‐adaptive sampling design
Authors: Pacifici Krishna , Reich Brian J. , Dorazio Robert M. , Conroy Michael J.
Published: October 2015

Spatially clustered populations create unique challenges for conservation monitoring programmes. Advances in methodology typically are focused on either the design or the modelling stage of the study but do not involve integration of both.

We integrate adaptive cluster sampling and spatial occupancy modelling by developing two models to handle the dependence induced by cluster sampling. We compare these models to scenarios using simple random sampling and traditional occupancy models via simulation and data collected on a rare plant species, Tamarix ramosissima, found in China.

Our simulations show a marked improvement in confidence interval coverage for the new models combined with cluster sampling compared to simple random sampling and traditional occupancy models, with greatest improvement in the presence of low detection probability and spatial correlation in occupancy.

Accounting for the design using the simple cluster random‐effects model reduces bias considerably, and full spatial modelling reduces bias further, especially for large n when the spatial covariance parameters can be estimated reliably. Both new models build on the strength of occupancy modelling and adaptive sampling and perform at least as well, and often better, than occupancy modelling alone.

We believe our approach is unique and potentially useful for a variety of studies directed at patchily distributed, clustered or rare species exhibiting spatial variation.
Peer‐led interventions to prevent tobacco, alcohol and/or drug use among young people aged 11–21 years: a systematic review and meta‐analysis
Authors: MacArthur Georgie J. , Harrison Sean , Caldwell Deborah M. , Hickman Matthew , Campbell Rona
Published: October 2015

Background and Aims

Peer‐led interventions may offer a beneficial approach in preventing substance use, but their impact has not yet been quantified. We conducted a systematic review to investigate and quantify the effect of peer‐led interventions that sought to prevent tobacco, alcohol and/or drug use among young people aged 11–21 years.

Methods

Medline, EMBASE, PsycINFO, CINAHL, ERIC and the Cochrane Library were searched from inception to July 2015 without language restriction. We included randomized controlled trials only. Screening and data extraction were conducted in duplicate and data from eligible studies were pooled in a random effects meta‐analysis.

Results

We identified 17 eligible studies, approximately half of which were school‐based studies targeting tobacco use among adolescents. Ten studies targeting tobacco use could be pooled, representing 13 706 young people in 220 schools. Meta‐analysis demonstrated that the odds of smoking were lower among those receiving the peer‐led intervention compared with control [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62–0.99, P = 0.040]. There was evidence of heterogeneity (I2 = 41%, χ2 15.17, P = 0.086). Pooling of six studies representing 1699 individuals in 66 schools demonstrated that peer‐led interventions were also associated with benefit in relation to alcohol use (OR = 0.80, 95% CI = 0.65–0.99, P = 0.036), while three studies (n = 976 students in 38 schools) suggested an association with lower odds of cannabis use (OR = 0.70, 0.50–0.97, P = 0.034). No studies were found that targeted other illicit drug use.

Conclusions

Peer interventions may be effective in preventing tobacco, alcohol and possibly cannabis use among adolescents, although the evidence base is limited overall, and is characterized mainly by small studies of low quality.
Transplacental Transfer of Interleukin‐1 Receptor Agonist and Antagonist Following Maternal Immune Activation
Authors: Girard Sylvie , Sebire Guillaume
Published: October 2015

Problem

Prenatal exposure to inflammation increases the incidence of neonatal brain injury. This raise the question whether maternally produced cytokines, especially interleukin (IL)‐1 elevated in pathological pregnancies and known to alter fetal development, can cross the placental barrier and affect the fetus directly.

Method of study

We addressed if IL‐1 agonist/antagonist could cross the placenta.

Results

Radiolabelled‐IL‐1 injected maternally reached the fetus in minimal amount. 3% of the amount detected within the placenta was transferred into the fetal liver and less than 1% recovered in the fetal brain 30 min after the injection Importantly, transfer of IL‐1 was not affected by maternal exposure to LPS. Maternal administration of IL‐1 receptor antagonist also reached the fetus in low concentration.

Conclusions

This suggests that minimal amount of maternally produced IL‐1 family members cross the placental barrier. Their negative effects are likely indirect, through their deleterious placental actions.
Suboptimal bonding impairs hormonal, epigenetic and neuronal development in preterm infants, but these impairments can be reversed
Authors: Kommers D , Oei G , Chen W , Feijs L , Bambang Oetomo S
Published: October 2015

This review aimed to raise awareness of the consequences of suboptimal bonding caused by prematurity. In addition to hypoxia–ischaemia, infection and malnutrition, suboptimal bonding is one of the many unnatural stimuli that preterm infants are exposed to, compromising their physiological development. However, the physiological consequences of suboptimal bonding are less frequently addressed in the literature than those of other threatening unnatural stimuli.

Conclusion

This review found that suboptimal bonding significantly impaired hormonal, epigenetic and neuronal development, but these impairments could be reversed by bonding interventions. This suggests that neonatal intensive care units should focus more on interventions that optimise bonding.
Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models
Authors: De Sousa Mendes Maïlys , Hirt Deborah , Vinot Cécile , Valade Elodie , Lui Gabrielle , Pressiat Claire , Bouazza Naïm , Foissac Frantz , Blanche Stephane , Lê Minh Patrick , Peytavin Gilles , Treluyer Jean‐Marc , Urien Saik , Benaboud Sihem
Published: October 2015

AIMS

Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively.

Methods

Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy–physiologically based pharmacokinetic (p‐PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models.

Results

Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo.

Conclusion

The integration of ex vivo human placental perfusion parameters in a p‐PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.
The Inhibitory Effect of Ciprofloxacin on the β‐Glucuronidase‐mediated Deconjugation of the Irinotecan Metabolite SN‐38‐G
Authors: Kodawara Takaaki , Higashi Takashi , Negoro Yutaka , Kamitani Yukio , Igarashi Toshiaki , Watanabe Kyohei , Tsukamoto Hitoshi , Yano Ryoichi , Masada Mikio , Iwasaki Hiromichi , Nakamura Toshiaki
Published: October 2015

The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. β‐Glucuronidase, an intestinal bacteria‐produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide‐conjugated drugs. In this study, we established an in vitro system to evaluate the β‐glucuronidase‐mediated deconjugation of the irinotecan metabolite SN‐38‐G to its active SN‐38 form and the effect of ciprofloxacin thereon. SN‐38 formation increased in a time‐dependent manner from 5 to 30 min. in the presence of β‐glucuronidase. Ciprofloxacin and phenolphthalein‐β‐d‐glucuronide (PhePG), a typical β‐glucuronidase substrate, significantly decreased SN‐38‐G deconjugation and, hence SN‐38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN‐38‐G to SN‐38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose‐dependent inhibitory effect on the β‐glucuronidase‐mediated conversion of SN‐38‐G to SN‐38 with a half‐maximal inhibitory concentration (IC50) value of 83.8 μM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non‐competitive manner, respectively. These findings suggest that the reduction in the serum SN‐38 concentration following co‐administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN‐38 through the non‐competitive inhibition of intestinal β‐glucuronidase‐mediated SN‐38‐G deconjugation.
Mechanism of Mcl‐1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation
Authors: Wang Anhui , Song Ting , Wang Ziqian , Liu Yubo , Fan Yudan , Zhang Yahui , Zhang Zhichao
Published: October 2015

Inhibition of interactions between Mcl‐1 and proapoptotic proteins is considered to be a therapeutic strategy to induce apoptosis in cancer cells. Here, we adopted molecular dynamics simulation with molecular mechanics–Poisson Boltzmann/surface area method (MM‐PB/SA) to study the inhibition mechanism of three Mcl‐1 inhibitors, compounds 1, 2 and 3. Analysis of energy components shows that the better binding free energy of compound 3 than compounds 1 and 2 is attributable to the van der Waals energy (ΔEvdw) and non‐polar solvation energy (ΔGnp) upon binding. In addition to the excellent agreement with previous experimentally determined affinities, our simulation results further show a bend of helix 4 on Mcl‐1 upon compound 3 binding, which is driven by hydrophobic interaction with residue Val253, leading to a narrowed BH3‐binding groove to impede PumaBH3 binding. The computational result is consistent with our competitive isothermal titration calorimetry (ITC) assays, which shows that the competitive ability of compound 3 toward Mcl‐1/PumaBH3 complex is improved beyond its direct binding affinity toward Mcl‐1 itself, and compound 3 exhibits much more efficiency to compete with PumaBH3 than compound 2. Our study provides a new strategy to improve inhibitory activity on Mcl‐1 based on the conformational dynamic change.
Sirtuins are Unaffected by PARP Inhibitors Containing Planar Nicotinamide Bioisosteres
Authors: Ekblad Torun , Schüler Herwig
Published: October 2015

PARP‐family ADP‐ribosyltransferases (PARPs) and sirtuin deacetylases all use NAD+ as cosubstrate for ADP‐ribosyl transfer. PARP inhibitors are important research tools and several are being evaluated in cancer treatment. With the exception of a few tankyrase inhibitors, all current PARP inhibitors mimic the nicotinamide moiety in NAD+ and block the nicotinamide binding pocket. We report here that while the activities of the four human sirtuin isoforms SIRT1, SIRT2, SIRT3 and SIRT6 are blocked by sirtuin inhibitor Ex527 in vitro, they are unaffected by the seven clinical and commonly used PARP inhibitors niraparib, olaparib, rucaparib, talazoparib, veliparib, PJ34, and XAV939. These findings indicate that PARP inhibitors containing planar nicotinamide mimetics do not bind to sirtuin cofactor sites. In conclusion, a simple commercially available assay can be used to rule out interference of novel PARP inhibitors with sirtuin NAD+ binding.
Synthesis, Antifolate and Anticancer Activities of N5‐Substituted 8,10‐Dideazatetrahydrofolate Analogues
Authors: Tian Chao , Zhang Zhili , Zhou Shouxin , Yuan Mengmeng , Wang Xiaowei , Liu Junyi
Published: October 2015

Based on our previous work, seven N5‐substituted 8,10‐dideazatetrahydrofolate analogues and one 8‐deazatetrahydrofolate analogue were designed and synthesized as human dihydrofolate reductase (hDHFR) inhibitors. All compounds were assayed versus DHFR and five different cancer cell lines. The biological assay indicated that replacing N10 with carbon would significantly increase inhibitory activities against DHFR and cytotoxicities against cancer cell lines. Compound 19a with 4‐amino and N5‐formyl showed great antitumour activities against HL‐60, Bel‐7402 and BGC823 which were much better than MTX.
An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAP™ and SocketKAGE™: part 2 – three‐dimensional alveolar bone volumetric analysis of CBCT imaging
Authors: Abdelhamid Alaa , Omran Mostafa , Bakhshalian Neema , Tarnow Dennis , Zadeh Homayoun H.
Published: October 2015

Objectives

The aims of this study were (i) to evaluate the efficacy of ridge preservation and repair procedures involving the application of SocketKAP™ and SocketKAGE™ devices following tooth removal and (ii) to evaluate alveolar bone volumetric changes at 6 months post‐extraction in intact sockets or those with facial wall dehiscence defects using 3‐dimensional pre‐ and postoperative CBCT data.

Materials and Methods

Thirty‐six patients required 61 teeth extracted. Five cohorts were established: Group A: Intact Socket Negative Control Group B: Intact Socket + SocketKAP™ Group C: Intact Socket Filled with Anorganic Bovine Bone Mineral (ABBM) + SocketKAP™ Group D: Facial Dehiscence Socket Negative Control Group E: Facial Dehiscence Socket Filled with ABBM + SocketKAP™ + SocketKAGE™. Preoperative CBCT scans were obtained followed by digital subtraction of the test teeth. At 6 months post‐extraction, another CBCT scan was obtained. The pre‐ and postoperative scans were then superimposed, allowing highly accurate quantitative determination of the 3D volumetric alveolar bone volume changes from baseline through 6 months.

Results

Significant volumetric bone loss occurred in all sockets, localized mainly in the 0–3 mm zone apical to the ridge crest. For intact sockets, SocketKAP™ + ABBM treatment led to a statistically significant greater percentage of remaining mineralized tissue volume when compared to negative control group. A significant difference favoring SocketKAP™ + SocketKAGE™ + ABBM treatment was observed for sockets with facial dehiscence defects compared to the negative control group.

Conclusions

SocketKAP™, with ABBM, appears effective in limiting post‐extraction volumetric bone loss in intact sockets, while SocketKAP™ + SocketKAGE + ABBM appears effective in limiting post‐extraction bone loss in sockets with dehiscence defects.
Blood flow‐restricted walking in older women: does the acute hormonal response associate with muscle hypertrophy?
Authors: Ozaki Hayao , Loenneke Jeremy P. , Abe Takashi
Published: October 2015

Low‐load exercise can increase serum hormones such as growth hormone (GH) concentration in young adults when combined with blood flow restriction (BFR), but it is unclear whether walking with BFR (BFR‐walk) can elevate them for older adults. Furthermore, it remained untested whether changes in these purported anabolic hormones contribute to BFR‐walk‐induced muscle hypertrophy. To examine the relationship between the acute and chronic effects of BFR‐walk, seven women (age: 64 ± 2 years) performed treadmill walking with (BFR‐walk) and without BFR (CON‐walk) at 45% of heart rate reserve for 20 min in a randomized crossover design. During BFR‐walk, subjects wore 5‐cm cuffs on the proximal part of the upper legs. Blood samples were taken before (PRE), immediately after (POST‐1) and 15 min post (POST‐2) exercise. There was a main effect of time for GH (P<0·01) with levels increasing following exercise. In addition, there was a condition and time main effect for insulin; with insulin increasing to a greater degree with BFR at POST‐2. Noradrenaline increased across time for both BFR‐walk (P = 0·012) and CON‐walk (P<0·001); but BFR‐walk induced greater elevations at POST‐1 and POST‐2. The change in GH, insulin and noradrenaline was not significantly correlated with BFR‐walk‐induced muscle hypertrophy. These preliminary results suggest that the BFR‐walk‐induced elevation in the purported anabolic hormones may not have a large impact on muscle growth.
High cut‐off dialysis in chronic haemodialysis patients
Authors: Girndt Matthias , Fiedler Roman , Martus Peter , Pawlak Michael , Storr Markus , Bohler Torsten , Glomb Marcus A. , Liehr Kristin , Henning Christian , Templin Markus , Trojanowicz Bogusz , Ulrich Christof , Werner Kristin , Zickler Daniel , Schindler Ralf
Published: October 2015

Background

Haemodialysis patients suffer from chronic systemic inflammation and high incidence of cardiovascular disease. One cause for this may be the failure of diseased kidneys to eliminate immune mediators. Current haemodialysis treatment achieves insufficient elimination of proteins in the molecular weight range 15–45 kD. Thus, high cut‐off dialysis might improve the inflammatory state.

Design

In this randomized crossover trial, 43 haemodialysis patients were treated for 3 weeks with high cut‐off or high‐flux dialysis. Inflammatory plasma mediators, monocyte subpopulation distribution and leucocyte gene expression were quantified.

Results

High cut‐off dialysis supplemented by a low‐flux filter did not influence the primary end‐point, expression density of CD162 on monocytes. Nevertheless, treatment reduced multiple immune mediators in plasma. Such reduction proved – at least for some markers – to be a sustained effect over the interdialytic interval. Thus, for example, soluble TNF‐receptor 1 concentration predialysis was reduced from median 13·3 (IQR 8·9–17·2) to 9·7 (IQR 7·5–13·2) ng/mL with high cut‐off while remaining constant with high‐flux treatment. The expression profile of multiple proinflammatory genes in leucocytes was significantly dampened. Treatment was well tolerated although albumin losses in high cut‐off dialysis would be prohibitive against long‐term use.

Conclusions

The study shows for the first time that a dampening effect of high cut‐off dialysis on systemic inflammation is achievable. Earlier studies had failed due to short study duration or insufficient dialysis efficacy. Removal of soluble mediators from the circulation influences cellular activation levels in leucocytes. Continued development of less albumin leaky membranes with similar cytokine elimination is justified.
Chronic myeloid leukemia in the Netherlands: a population‐based study on incidence, treatment, and survival in 3585 patients from 1989 to 2012
Authors: Thielen Noortje , Visser Otto , Ossenkoppele Gert , Janssen Jeroen
Published: October 2015

Objective

To assess the impact and results of treatment of CML in the general population, we conducted a population‐based, nationwide study on 3585 CML patients diagnosed between 1989 and 2012 in the Netherlands.

Methods

Patient demographics were obtained from the Netherlands Cancer Registry. Information on age, gender, year of diagnosis, first treatment, and date of death were recorded. Overall survival (OS) was adjusted for death rates in the normal population.

Results

Incidence in males decreased slightly from 1.2 per 100.000 person years (PY) in 1989–2000 to 0.9 in 2001–2012. For females, incidence remained stable with 0.7 per 100.000 PY in both periods. Incidence was age dependent and highest in males in the last decades of life. Treatment before 2000 mainly consisted of chemotherapy, while after 2007 TKI use was 88%. Five‐year relative survival was only 36% before the introduction of TKIs but significantly increased to 79% after the introduction of TKI.

Conclusions

This study gives insight into CML incidence, treatment, and survival in routine care in the Netherlands. Although OS improved since the introduction of TKIs, there is still room for further improvement.
Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early‐stage Parkinson's disease
Authors: Reimão S. , Ferreira S. , Nunes R. G , Pita Lobo P. , Neutel D. , Abreu D. , Gonçalves N. , Campos J. , Ferreira J. J.
Published: October 2015

Background and purpose

Magnetic resonance (MR) studies have demonstrated a significant reduction of neuromelanin in the substantia nigra (SN) of Parkinson's disease (PD) patients with high accuracy for differential diagnosis compared to non‐PD controls and essential tremor. However, studies state that not knowing how paramagnetic effects of iron influence neuromelanin signal is a limitation. In this study a neuromelanin‐sensitive MR sequence was combined with T2* relaxometry iron quantification analysis to study the SN of early‐stage PD patients to investigate the correlation between these parameters.

Methods

The inclusion criteria were untreated de novo PD patients and a 2–5 year disease duration (early PD); in addition, age‐matched controls were enrolled. These were studied at 3.0 T with a high‐resolution T1‐weighted MR sequence to visualize neuromelanin and a relaxometry sequence for iron quantification. The primary outcome was the correlation of the width of the neuromelanin high signal region and the T2* values in the lateral, central and medial segments of the SN.

Results

Very weak correlations of T2* values with neuromelanin width, positive for global and negative for the medial and lateral SN segments, were found in both PD groups and control subjects. The SN neuromelanin width was markedly reduced in the de novo and early PD groups compared with controls in all SN segments, but no significant difference in T2* values was found between the groups.

Conclusions

The SN neuromelanin signal does not have a significant correlation with iron content in PD patients or controls. The neuromelanin MR signal reduction in PD does not seem to be significantly influenced by paramagnetic iron effects.
Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection
Authors: Mowry E. M. , Pelletier D. , Gao Z. , Howell M. D. , Zamvil S. S. , Waubant E.
Published: October 2015

Background and purpose

Vitamin D status has been associated with inflammatory activity in multiple sclerosis (MS), but it is not known if it is associated with gray matter volume, the loss of which predicts long‐term disability in MS. The association of vitamin D levels with brain volume measures and inflammatory activity in patients with clinically isolated syndrome (CIS) was investigated.

Methods

In the phase 2 CIS trial of atorvastatin, 25‐hydroxyvitamin D levels were evaluated for their age‐adjusted associations with normalized gray matter and brain parenchymal volumes on brain magnetic resonance imaging (MRI). The relationships between 25‐hydroxyvitamin D levels and clinical and MRI measures of inflammatory activity were also assessed.

Results

In 65 patients in this substudy, each 25 nmol/l higher 25‐hydroxyvitamin D level was associated with 7.8 ml higher gray matter volume (95% confidence interval 1.0, 14.6, P = 0.025). There was a tendency for an inverse association of average 25‐hydroxyvitamin D levels and the composite end‐point of ≥3 new brain T2 lesions or ≥1 relapse within a year (odds ratio per 25 nmol/l higher 25‐hydroxyvitamin D level 0.66, 95% confidence interval 0.41, 1.08, P = 0.096).

Conclusions

Vitamin D status may impact neurodegeneration after CIS, although these results should be replicated in a second study. If confirmed in clinical trials, vitamin D supplementation may reduce long‐term disability.
Differential spectral quantitative electroencephalography patterns between control and Parkinson's disease cohorts
Authors: Caviness J. N. , Utianski R. L. , Hentz J. G. , Beach T. G. , Dugger B. N. , Shill H. A. , Driver‐Dunckley E. D. , Sabbagh M. N. , Mehta S. , Adler C. H.
Published: October 2015

Background and purpose

It is believed that progressive Lewy‐type synucleinopathy (LTS) is primarily responsible for the worsening of motor and non‐motor Parkinson's disease (PD) signs and symptoms. Characterization of quantitative electroencephalography (QEEG) abnormalities across the spectrum of LTS to PD dementia (PD‐D) may provide insight into the pathophysiology of PD cortical dysfunction. Here our enlarged EEG database was leveraged to characterize spectral QEEG abnormalities in asymptomatic autopsy‐defined groups of control participants and incidental Lewy body disease (ILBD) and three clinically defined groups of participants with PD (cognitively normal PD, mild cognitive impairment PD, and PD‐D).

Methods

The PD cohort was studied as part of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). AZSAND utilizes its Brain and Body Donation Program to perform prospective, standardized, regular longitudinal pre‐mortem assessments until death. Resting EEG from subjects was analyzed for spectral domain QEEG measures of background rhythm frequency and global relative power in delta, theta, alpha and beta bands.

Results

The various spectral QEEG measures showed differential changes specific to the groups compared. Important findings were background rhythm frequency showing the most pairwise differences across the groups, and this also was the only significant difference between control and ILBD. An increase in delta bandpower was characteristic of worsening cognitive deficits.

Conclusions

Different patterns of change amongst QEEG measures across LTS and PD cognitive states suggest that they correlate with heterogeneous pathophysiologies of cortical dysfunction within the PD clinical spectrum. In addition, the biomarker application of a specific spectral QEEG measure needs to be selectively suited to its study purpose.
Performance of cognitive tests, individually and combined, for the detection of cognitive disorders amongst community‐dwelling elderly people with memory complaints: the EVATEM study
Authors: Vannier‐Nitenberg C. , Dauphinot V. , Bongue B. , Sass C. , Bathsavanis A. , Rouch I. , Deville N. , Beauchet O. , Krolak‐Salmon P. , Fantino B.
Published: October 2015

Background and purpose

Dementia is a leading cause of dependence amongst the aged population. Early identification of cognitive impairment could help to delay advanced stages of dependence. This study aimed at assessing the performance of three neuropsychological tests to detect cognitive disorders in elderly subjects with memory complaints.

Methods

The EVATEM study is a prospective multicentre cohort with a 1‐year follow‐up. Subjects with memory complaints were selected during preventive health examinations, and three neuropsychological tests (five‐word, cognitive disorders examination, verbal fluency) were administered. Two groups were identified in memory clinics: (i) cognitively healthy individuals (CHI) and (ii) mild cognitive impairment or demented individuals (MCI‐DI). Cross‐sectional analyses were performed on data at inclusion. The relationship between the diagnosis of MCI‐DI/CHI and the neuropsychological tests was assessed using logistic regressions. The performance of the neuropsychological tests, individually and combined, to detect cognitive disorders was calculated.

Results

Of 585 subjects, 31.11% had cognitive disorders (MCI, 176 subjects; DI, six subjects). Amongst the three tests studied, the odds ratio for MCI‐DI was higher for the five‐word test <10 [odds ratio 3.2 (1.81; 5.63)]. The best performance was observed when the three tests were combined: specificity 90.5% and sensitivity 42.4% compared to respectively 89.2% and 28.3% for the five‐word test.

Conclusions

Despite the poor sensitivity of the five‐word test, it seems to be the most adapted for the diagnosis of MCI‐DI in older adults with a memory complaint, in prevention centres, taking into account its high specificity and its rapid administration compared to the other tests.
Hydration and collateral flow in acute stroke
Authors: Liebeskind D. S.
Published: October 2015

Click here to view the accompanying paper in this issue.
Factors associated with dust dispersed in the air of indoor riding arenas
Authors: Lühe T. , Mielenz N. , Schulz J. , Dreyer‐Rendelsmann C. , Kemper N.
Published: October 2015

Reasons for performing study

Environmental factors contribute to respiratory diseases in horses and man. During exercise, equine ventilation is increased, potentially increasing exposure of the airways to inhaled particulates. Currently, there is very little information on the quality of air in riding arenas.

Objectives

To evaluate air quality and dust particle concentrations in indoor riding arenas before and after use for riding.

Study design

Longitudinal study.

Methods

Air quality was assessed in 4 indoor riding arenas in Saxony‐Anhalt, Germany on a monthly basis for 1 year. Concentrations of particles in 6 particle fractions from 0.3 to 5.0 μm were measured in air collected at 4 points in the riding arenas approximately at the height of the horses’ (1.5 m) and riders’ noses (2.5 m), before and after the arenas were used by one horse performing standardised riding session.

Results

There were significant differences in the numbers of particles between the arenas within months and between months within the arenas. Particle numbers were significantly influenced by the month and activities in the arenas before and after riding. The effect of the month on differences in the dust concentration may relate to surface watering. A significant increase in numbers of particles was observed after the riding session. Significant interactions were found between measuring heights and month within arena (P<0.01) and there was an interaction between measuring height and time points (before and after riding, P = 0.02).

Conclusions

The amount of dust dispersed in the air increases during riding in indoor arenas and this appears to be influenced by footing material, direct connections between the arena and stables and season, possibly reflecting surface watering practices.
Neuronal chromatolysis in the subgemmal plexus of gustatory papillae in horses with grass sickness
Authors: McGorum B. C. , Pirie R. S. , Shaw D. , Macintyre N. , Cox A.
Published: October 2015

Reasons for performing study

Diagnosis of equine grass sickness (EGS) can be challenging. We hypothesised that subgemmal plexus neurons are chromatolytic in EGS. If correct, histopathological examination of gustatory papillae biopsies could aid premortem diagnosis of EGS, and EGS could represent a spontaneous model of subgemmal neuronal chromatolysis to facilitate study of the pathology of structures involved in taste.

Objective

To compare subgemmal plexi and gustatory papillae in EGS and control horses.

Study design

Observational study.

Methods

Conventional histology and immunohistochemistry were used to compare subgemmal plexi and gustatory papillae in post mortem samples from 10 EGS and 13 control horses.

Results

Chromatolytic neurons were present in all 57 EGS sections which had identifiable neurons, and in only one of 57 control sections. Blinded examination of all haematoxylin‐eosin stained sections from each horse for chromatolysis facilitated accurate differentiation of EGS and control horses, with a sensitivity of 100% (95% confidence interval 93.7–100) and specificity of 98.2% (90.6–100) for diagnosing EGS; however, the presence of chromatolytic neurons in one control section indicated that multiple sections per horse must be analysed to achieve diagnostic accuracy. Equine grass sickness was not associated with alterations in taste bud density or morphology, proportion of taste buds with neurofilament immunopositive intragemmal axons or proportion of taste buds containing cells undergoing apoptosis, suggesting taste buds had adequate neurotrophic support at the time of sampling. Horses with EGS had no detectable alteration in lingual gland morphology, but had increased proportions of apoptotic lingual serous gland cells.

Conclusions

While identification of chromatolytic subgemmal neurons in post mortem samples correctly differentiated EGS and control horses, further study is required to evaluate this technique for premortem EGS diagnosis. Equine grass sickness represents a spontaneous model of subgemmal neuronal chromatolysis that facilitates study of the pathology of structures involved in taste.
Cytokine, catabolic enzyme and structural matrix gene expression in synovial fluid following intra‐articular administration of triamcinolone acetonide in exercised horses
Authors: Knych H. K. , Vidal M. A. , Chouicha N. , Mitchell M. , Kass P. H.
Published: October 2015

Reason for performing study

The frequent use of intra‐articular triamcinolone acetonide (TA) in performance horses warrants further study of the duration of as well as the beneficial and detrimental effects on gene expression associated with administration.

Objectives

To assess the effects of intra‐articular administration ofTAon the expression of selected anti‐ and proinflammatory and structural matrix genes following its administration into joints of exercised Thoroughbred horses and to correlate these effects with plasma and synovial fluid drug concentrations.

Study design

Block design experiment.

Methods

Eight exercised horses received a single intra‐articular administration of 9 mg ofTA. Synovial fluid samples were collected from the treated and contralateral joints prior to and up to 49 days following drug administration. Microarray and quantitative reverse transcription polymerase chain reaction analysis were used to assess changes in expression levels of various inflammatory and structural genes post drug administration.

Results

Drug concentrations in plasma and synovial fluid, were no longer quantifiable by 6 and 28 days following drug administration respectively. In total, the expression level of 5490 genes were significantly altered on micro array analysis, following intra‐articularTAadministration. Of the genes selected for further study by quantitative reverse transcription polymerase chain reaction analysis, significant changes in inflammatory genes (annexin type 1, cyclooxygenase‐1 and tumour necrosis factor stimulated gene 6) and structural genes (collagen and aggrecan) were noted.

Conclusions

This study supports the use of synovial fluid as a biological matrix for studying the effects of corticosteroids on gene expression. For the majority of genes studied the effects on expression relative to baseline for both inflammatory and matrix genes were prolonged relative to plasma and synovial fluidTAconcentrations. Downregulation of collagen gene expression warrants the careful use ofTAin horses.
Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands
Authors: Li Yong , Stoll Stefan W. , Sekhon Sahil , Talsma Caroline , Camhi Maya I. , Jones Jennifer L. , Lambert Sylviane , Marley Hue , Rittié Laure , Grachtchouk Marina , Fritz Yi , Ward Nicole L. , Elder James T.
Published: October 2015

To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5′ and 3′ untranslated region sequences (AREG‐UTR) led to a >10‐fold increase in hAREG expression compared to an otherwise‐identical construct containing only the coding region (AREG‐CDR). AREG‐UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG‐CDR mice. Histologically, AREG‐UTR mice presented with marked epidermal hyperplasia of tail skin (2.1‐fold increase in epidermal thickness with a 9.5‐fold increase in Ki‐67+ cells) accompanied by significantly increased CD4+ T‐cell infiltration. Dorsal skin of AREG‐UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG‐UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki‐67+ cells. To determine the response of AREG‐UTR animals to a pro‐inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG‐UTR and wild type mice (1.7‐ and 2.2‐fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.
Discovery of a Partner Affair and Major Depressive Episode in a Probability Sample of Married or Cohabiting Adults
Authors: Whisman Mark A.
Published: October 2015

Prior research has found that humiliating marital events are associated with depression. Building on this research, the current study investigated the association between one specific humiliating marital event—discovering that one's partner had an affair—and past‐year major depressive episode (MDE) in a probability sample of married or cohabiting men and women who were at high risk for depression based on the criterion that they scored below the midpoint on a measure of marital satisfaction (N = 227). Results indicate that (i) women were more likely than men to report discovering their partner had an affair in the prior 12 months; (ii) discovering a partner affair was associated with a higher prevalence of past‐year MDE and a lower level of marital adjustment; and (iii) the association between discovering a partner affair and MDE remained statistically significant when holding constant demographic variables and marital adjustment. These results support continued investigation into the impact that finding out about an affair has on the mental health of the person discovering a partner affair.
Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling
Authors: Kittas Aristotelis , Delobelle Aurélien , Schmitt Sabrina , Breuhahn Kai , Guziolowski Carito , Grabe Niels
Published: October 2015

An effective means to analyze mRNA expression data is to take advantage of established knowledge from pathway databases, using methods such as pathway‐enrichment analyses. However, pathway databases are not case‐specific and expression data could be used to infer gene‐regulation patterns in the context of specific pathways. In addition, canonical pathways may not always describe the signaling mechanisms properly, because interactions can frequently occur between genes in different pathways. Relatively few methods have been proposed to date for generating and analyzing such networks, preserving the causality between gene interactions and reasoning over the qualitative logic of regulatory effects. We present an algorithm (MCWalk) integrated with a logic programming approach, to discover subgraphs in large‐scale signaling networks by random walks in a fully automated pipeline. As an exemplary application, we uncover the signal transduction mechanisms in a gene interaction network describing hepatocyte growth factor‐stimulated cell migration and proliferation from gene‐expression measured with microarray and RT‐qPCR using in‐house perturbation experiments in a keratinocyte‐fibroblast co‐culture. The resulting subgraphs illustrate possible associations of hepatocyte growth factor receptor c‐Met nodes, differentially expressed genes and cellular states. Using perturbation experiments and Answer Set programming, we are able to select those which are more consistent with the experimental data. We discover key regulator nodes by measuring the frequency with which they are traversed when connecting signaling between receptors and significantly regulated genes and predict their expression‐shift consistently with the measured data. The Java implementation of MCWalk is publicly available under the MIT license at: https://bitbucket.org/akittas/biosubg.
Tissue chemistry and morphology affect root decomposition of perennial bioenergy grasses on sandy soil in a sub‐tropical environment
Authors: Liang Xi , Erickson John E. , Silveira Maria L. , Sollenberger Lynn E. , Rowland Diane L.
Published: October 2015

Second‐generation biofuels and bio‐based products derived from lignocellulosic biomass are likely to replace current fuels derived from simple sugars and starch because of greater yield potential and less competition with food production. Besides the high aboveground biomass production, these bioenergy grasses also exhibit extensive root systems. The decomposition of root biomass greatly influences nutrient cycling and microbial activity and subsequent accumulation of carbon (C) in the soil. The objective of this research was thus to characterize root morphological and chemical differences in six perennial grass species in order to better understand root decomposition and belowground C cycling of these bioenergy cropping systems. Giant reed (Arundo donax), elephantgrass (Pennisetum purpureum), energycane (Saccharum spp.), sugarcane (Saccharum spp.), sweetcane (Saccharum arundinaceum), and giant miscanthus (Miscanthus × giganteus) were established in Fall 2008 in research plots near Gainesville, Florida. Root decomposition rates were measured in situ from root decomposition bags over 12 months along with initial and final root tissue composition. Root potential decomposition rate constant (K) was higher in elephantgrass (3.64 g kg−1 day−1) and sweetcane (2.77 g kg−1 day−1) than in sugarcane (1.62 g kg−1 day−1) and energycane (1.48 g kg−1 day−1). Notably, K was positively related to initial root tissue total C (Total C), total fiber glucose (TFG), total fiber xylose (TFX), and total fiber carbohydrate (TFC) concentrations, but negatively related to total fiber arabinose (TFA) and lignin (TL) concentrations and specific root volume (SRV). Among the six species, elephantgrass exhibited root traits most favorable for fast decomposition: high TFG, high TFX, high TFC, high specific root length (SRL), and a low SRV, whereas giant reed, sugarcane, and energycane exhibited slow decomposition rates and the corresponding root traits. Thus, despite similar aboveground biomass yields in many cases, these species are likely to differentially affect soil C accumulation.