bluuebunny/crossref_metadata_2025 huggingface dataset:
IntSide: a web server for the chemical and biological examination of drug side effects
Authors: Juan-Blanco Teresa , Duran-Frigola Miquel , Aloy Patrick
Published: October 2014

Summary: Drug side effects are one of the main health threats worldwide, and an important obstacle in drug development. Understanding how adverse reactions occur requires knowledge on drug mechanisms at the molecular level. Despite recent advances, the need for tools and methods that facilitate side effect anticipation still remains. Here, we present IntSide, a web server that integrates chemical and biological information to elucidate the molecular mechanisms underlying drug side effects. IntSide currently catalogs 1175 side effects caused by 996 drugs, associated with drug features divided into eight categories, belonging to either biology or chemistry. On the biological side, IntSide reports drug targets and off-targets, pathways, molecular functions and biological processes. From a chemical viewpoint, it includes molecular fingerprints, scaffolds and chemical entities. Finally, we also integrate additional biological data, such as protein interactions and disease-related genes, to facilitate mechanistic interpretations.

Availability and implementation: Our data and web resource are available online (http://intside.irbbarcelona.org/).

Contact:  patrick.aloy@irbbarcelona.org

Supplementary information:  Supplementary Data are available at Bioinformatics online.
Therapeutic uses of anti-α4-integrin (anti-VLA-4) antibodies in multiple sclerosis
Authors: Schwab Nicholas , Schneider-Hohendorf Tilman , Wiendl Heinz
Published: October 2014

Multiple sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very late antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4-mediated immune cell adhesion to the endothelium of the blood–brain barrier (BBB) alleviates pathogenic processes of MS and, therefore, reduces disease severity and burden. Not all approaches to treat additional immune-mediated disorders (e.g. Rasmussen encephalitis and neuromyelitis optica) with natalizumab have been successful, but allowed researchers to gain additional insight into mechanisms of specific immune cell subsets’ migration through the BBB in the human system. While the long-term efficacy and general tolerability of natalizumab in MS are clear, the over 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) have been of great concern and methods of risk stratification in patients have become a major area of research. Modern risk stratification includes established factors such as treatment duration, previous immune-suppressive therapy, and anti-John Cunningham virus (JCV) antibody seropositivity, but also experimental factors such as anti-JCV antibody titers and levels of L-selectin. Today, anti-VLA-4 therapy is reserved for patients with highly active relapsing-remitting MS and patients are monitored closely for early signs of potential PML.
Goals, Trust, Participation, and Feedback: Linking Internal Management With Performance Outcomes
Authors: Favero Nathan , Meier Kenneth J. , O’Toole Laurence J.
Published: October 2014

Much recent work in the study of public administration has emphasized new challenges and relatively unusual aspects of management. However, it is likely that the core features of traditional public administration play a crucial role, particularly regarding the delivery of performance. The most venerable of these aspects of public management have to do with “internal” management. We focus here on a cluster of key, intertwined management practices: setting challenging but feasible goals, building trust through credible commitments, encouraging employee participation, and providing feedback. We examine the relationship between such internal management at the mid-level, as perceived by subordinates rather than the managers themselves, and educational performance for more than 1,100 schools in the New York City school system over a 3-year period. The results indicate that internal management matters, often sizably, for delivering educational outcomes. The findings are robust to autoregressive specifications and the purging of halo effects, and they hold across multiple performance measures. Managers’ setting challenging goals appears to be especially important in generating educational results.
On the observability of coupled dark energy with cosmic voids
Authors: Sutter P. M. , Carlesi Edoardo , Wandelt Benjamin D. , Knebe Alexander
Published: October 2014

Taking N-body simulations with volumes and particle densities tuned to match the sloan digital sky survey DR7 spectroscopic main sample, we assess the ability of current void catalogues to distinguish a model of coupled dark matter–dark energy from Λ cold dark matter cosmology using properties of cosmic voids. Identifying voids with the vide toolkit, we find no statistically significant differences in the ellipticities, but find that coupling produces a population of significantly larger voids, possibly explaining the recent result of Tavasoli et al. In addition, we use the universal density profile of Hamaus et al. to quantify the relationship between coupling and density profile shape, finding that the coupling produces broader, shallower, undercompensated profiles for large voids by thinning the walls between adjacent medium-scale voids. We find that these differences are potentially measurable with existing void catalogues once effects from survey geometries and peculiar velocities are taken into account.
Magnetic spiral arms and galactic outflows
Authors: Chamandy Luke , Shukurov Anvar , Subramanian Kandaswamy
Published: October 2014

Galactic magnetic arms have been observed between the gaseous arms of some spiral galaxies; their origin remains unclear. We suggest that magnetic spiral arms can be naturally generated in the interarm regions because the galactic fountain flow or wind is likely to be weaker there than in the arms. Galactic outflows lead to two countervailing effects: removal of small-scale magnetic helicity, which helps to avert catastrophic quenching of the dynamo, and advection of the large-scale magnetic field, which suppresses dynamo action. For realistic galactic parameters, the net consequence of outflows being stronger in the gaseous arms is higher saturation large-scale field strengths in the interarm regions as compared to in the arms. By incorporating rather realistic models of spiral structure and evolution into our dynamo models, an interlaced pattern of magnetic and gaseous arms can be produced.
The Weng'an biota and the Ediacaran radiation of multicellular eukaryotes
Authors: Xiao Shuhai , Muscente A. D. , Chen Lei , Zhou Chuanming , Schiffbauer James D. , Wood Andrew D. , Polys Nicholas F. , Yuan Xunlai
Published: October 2014

The rise of multicellularity represents a major evolutionary transition and it occurred independently in multiple eukaryote clades. Although simple multicellular organisms may have evolved in the Mesoproterozoic Era or even earlier, complex multicellular eukaryotes began to diversify only in the Ediacaran Period, just before the Cambrian explosion. Thus, the Ediacaran fossil record can provide key paleontological evidence about the early radiation of multicellular eukaryotes that ultimately culminated in the Cambrian explosion. The Ediacaran Weng'an biota in South China hosts exceptionally preserved eukaryote fossils, including various acanthomorphic acritarchs, pseudoparenchymatous thalli, tubular microfossils, and spheroidal fossils such as Megasphaera, Helicoforamina, Spiralicellula, and Caveasphaera. Many of these fossils have been interpreted as multicellular eukaryotes, although alternative interpretations have also been proposed. In this review, we critically examine these various interpretations, focusing particularly on Megasphaera, which has been variously interpreted as a sulfur-oxidizing bacterium, a unicellular protist, a mesomycetozoean-like holozoan, a volvocine green alga, a stem-group animal, or a crown-group animal. We conclude that Megasphaera is a multicellular eukaryote with evidence for cell-to-cell adhesion, a flexible membrane unconstrained by a rigid cell wall, spatial cellular differentiation, germ–soma separation, and programmed cell death. These features are inconsistent with the bacterium, unicellular protist, and mesomycetozoean-like holozoan interpretations. Thus, the surviving hypotheses, particularly the stem-group animal and algal interpretations, should be further tested with additional evidence. The Weng'an biota also hosts cellularly differentiated pseudoparenchymatous thalli with specialized reproductive structures indicative of an affinity with florideophyte red algae. The other Weng'an fossils reviewed here may also be multicellular eukaryotes, although direct cellular evidence is lacking in some and phylogenetic affinities are poorly constrained in others. The Weng'an biota offers many research opportunities to resolve the life histories and phylogenetic diversity of early multicellular eukaryotes and to illuminate the evolutionary prelude to the Cambrian explosion.
Recent experimental progress of fractional quantum Hall effect: 5/2 filling state and graphene
Authors: Lin Xi , Du Ruirui , Xie Xincheng
Published: October 2014

The phenomenon of fractional quantum Hall effect (FQHE) was first experimentally observed 33 years ago. FQHE involves strong Coulomb interactions and correlations among the electrons, which leads to quasiparticles with fractional elementary charge. Three decades later, the field of FQHE is still active with new discoveries and new technical developments. A significant portion of attention in FQHE has been dedicated to filling factor 5/2 state, for its unusual even denominator and possible application in topological quantum computation. Traditionally, FQHE has been observed in high-mobility GaAs heterostructure, but new materials such as graphene also open up a new area for FQHE. This review focuses on recent progress of FQHE at 5/2 state and FQHE in graphene.
Thiopseudomonas denitrificans gen. nov., sp. nov., isolated from anaerobic activated sludge
Authors: Tan Wen-Bo , Jiang Zhao , Chen Chuan , Yuan Ye , Gao Ling-Fang , Wang Hong-Fei , Cheng Juan , Li Wen-Jun , Wang Ai-Jie
Published: October 2014

A Gram-staining-negative, rod-shaped, motile and facultatively anaerobic bacterial strain, designated X2T, was isolated from the sludge of an anaerobic, denitrifying, sulfide-removal bioreactor, and found to oxidize sulfide anaerobically with nitrate as electron acceptor. The strain grew at salinities of 0–3 % (w/v) NaCl (optimum, 0–1 %). Growth occurred at pH 6.0–10.0 (optimum, pH 8.0) and 10–37 °C (optimum, 30 °C). The genomic DNA G+C content was 59 mol%. Q-8 and Q-9 were detected as the respiratory quinones. The major fatty acids (>10 %) were C16 : 1ω7c and/or C16 : 1ω6c, C18 : 1ω7c and C16 : 0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and one unidentified phospholipid. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain X2T formed a novel clade within the family

Pseudomonadaceae

, with the highest sequence similarity to

Pseudomonas caeni

KCTC 22292T (93.5 %). On the basis of phenotypic, chemotaxonomic and phylogenetic characteristics, it is proposed that this strain represents novel genus and species within the family

Pseudomonadaceae

, for which the name Thiopseudomonas denitrificans gen. nov., sp. nov. is proposed. The type strain is X2T ( = CCTCC M 2013362T = DSM 28679T = KCTC 42076T).
Making sense of RNA-Seq data: from low-level processing to functional analysis
Authors: Moskvin Oleg V. , McIlwain Sean , Ong Irene M.
Published: October 2014

Numerous methods of RNA-Seq data analysis have been developed, and there are more under active development. In this paper, our focus is on evaluating the impact of each processing stage; from pre-processing of sequencing reads to alignment/counting to count normalization to differential expression testing to downstream functional analysis, on the inferred functional pattern of biological response. We assess the impact of 6,912 combinations of technical and biological factors on the resulting signature of transcriptomic functional response. Given the absence of the ground truth, we use two complementary evaluation criteria: a) consistency of the functional patterns identified in two similar comparisons, namely effects of a naturally-toxic medium and a medium with artificially reconstituted toxicity, and b) consistency of results in RNA-Seq and microarray versions of the same study. Our results show that despite high variability at the low-level processing stage (read pre-processing, alignment and counting) and the differential expression calling stage, their impact on the inferred pattern of biological response was surprisingly low; they were instead overshadowed by the choice of the functional enrichment method. The latter have an impact comparable in magnitude to the impact of biological factorsper se.
Using more than the oldest fossils: Dating Osmundaceae by three Bayesian clock approaches
Authors: Grimm Guido , Kapli Pashalia , Bomfleur Benjamin , McLoughlin Stephen , Renner Susanne S
Published: October 2014

A major concern in molecular clock dating is how to use information from the fossil record to calibrate genetic distances from DNA sequences. Here we apply three Bayesian dating methods that differ in how calibration is achieved--"node dating" (ND) in BEAST, "total evidence" (TE) dating in MrBayes, and the "fossilized birth-death" (FBD) in FDPPDiv--to infer divergence times in the Osmundaceae or royal ferns. Osmundaceae have 13 species in four genera, two mainly in the Northern Hemisphere and two in South Africa and Australasia; they are the sister clade to the remaining leptosporangiate ferns. Their fossil record consists of at least 150 species in ~17 genera and three extinct families. For ND, we used the five oldest fossils, while for TE and FBD dating, which do not require forcing fossils to nodes and thus can use more fossils, we included up to 36 rhizome and frond compression/impression fossils, which for TE dating were scored for 33 morphological characters. We also subsampled 10%, 25%, and 50% of the 36 fossils to assess model sensitivity. FBD-derived divergence dates were generally greater than ages inferred from ND dating; two of seven TE-derived ages agreed with FBD-obtained ages, the others were much younger or much older than ND or FBD ages. We favour the FBD-derived ages because they best match the Osmundales fossil record (including Triassic fossils not used in our study). Under the preferred model, the clade encompassing extant Osmundaceae (and many fossils) dates to the latest Palaeozoic to Early Triassic; divergences of the extant species occurred during the Neogene. Under the assumption of constant speciation and extinction rates, FBD yielded 0.0299 (0.0099--0.0549) and 0.0240 (0.0039--0.0495) for these rates, whereas neontological data yielded 0.0314 and 0.0339. However, FBD estimates of speciation and extinction are sensitive to violations in the assumption of continuous fossil sampling, therefore these estimates should be treated with caution.
The Gentio-Oligosaccharide Gentiobiose Functions in the Modulation of Bud Dormancy in the Herbaceous PerennialGentiana
Authors: Takahashi Hideyuki , Imamura Tomohiro , Konno Naotake , Takeda Takumi , Fujita Kohei , Konishi Teruko , Nishihara Masahiro , Uchimiya Hirofumi
Published: October 2014

Bud dormancy is an adaptive strategy that perennials use to survive unfavorable conditions. Gentians (Gentiana), popular alpine flowers and ornamentals, produce overwintering buds (OWBs) that can persist through the winter, but the mechanisms regulating dormancy are currently unclear. In this study, we conducted targeted metabolome analysis to obtain clues about the metabolic mechanisms involved in regulating OWB dormancy. Multivariate analysis of metabolite profiles revealed metabolite patterns characteristic of dormant states. The concentrations of gentiobiose [β-d-Glcp-(1→6)-d-Glc] and gentianose [β-d-Glcp-(1→6)-d-Glc-(1→2)-d-Fru] significantly varied depending on the stage of OWB dormancy, and the gentiobiose concentration increased prior to budbreak. Both activation of invertase and inactivation of β-glucosidase resulted in gentiobiose accumulation in ecodormant OWBs, suggesting that gentiobiose is seldom used as an energy source but is involved in signaling pathways. Furthermore, treatment with exogenous gentiobiose induced budbreak in OWBs cultured in vitro, with increased concentrations of sulfur-containing amino acids, GSH, and ascorbate (AsA), as well as increased expression levels of the corresponding genes. Inhibition of GSH synthesis suppressed gentiobiose-induced budbreak accompanied by decreases in GSH and AsA concentrations and redox status. These results indicate that gentiobiose, a rare disaccharide, acts as a signal for dormancy release of gentian OWBs through the AsA-GSH cycle.
Interaction of morphology, thermal physiology and burrowing performance during the evolution of fossoriality in Gymnophthalmini lizards
Authors: Camacho Agustín , Pavão Rodrigo , Moreira Camila Nascimento , Pinto Ana Carolina B. C. Fonseca , Navas Carlos A. , Rodrigues Miguel Trefaut
Published: October 2014

The evolution of fossoriality in Squamata often leads to a phenotypic syndrome involving snake‐like body form, relatively low preferred temperature (TP) and low critical maximum temperatures (CTmax). However, how traits interacted among them and with the environment during the evolution of such syndrome remains poorly understood.

We studied this process in ten species of gymnophthalmid lizards from the Brazilian Caatinga representing one full transition from typical lacertoid species to fossorial snake‐like (FSL) ones. We tested whether different morphotypes exhibited different burrowing performances in response to heat, and also differentTPand CTmax. Then, we estimated how changes in burrowing performance would relate to thermoregulation costs in terms of the number of daily hours for which preferred temperatures are available and of risk of overheating.

Fossorial snake‐like species burrowed deeper, exhibited lowerTPbut kept very high CTmax, comparable to lacertoid species. A better burrowing performance and lowerTPallowed increasing the daily amount of time during whichTPwas accessible within the soil of the study region. In addition, temperatures above CTmaxof the studied species were present down to 5 cm deep, suggesting that just burrowing does not protect against exposure to extreme temperatures in species that are surface‐active during the day (all lacertoids and some FSL). Nonetheless, FSL species active at cool hours of the day exhibited lower CTmaxthan diurnal and syntopic, lacertoid and FSL species.

Based on our data and previous literature, we propose a sequential explanation for the acquisition of the fossorial syndrome in Squamata.
Maternal effects and population regulation: maternal density‐induced reproduction suppression impairs offspring capacity in response to immediate environment in root voles Microtus oeconomus
Authors: Bian Jiang‐Hui , Du Shou‐Yang , Wu Yan , Cao Yi‐Fan , Nie Xu‐Heng , He Hui , You Zhi‐Bing
Published: October 2014

The hypothesis that maternal effects act as an adaptive bridge in translating maternal environments into offspring phenotypes, and thereby affecting population dynamics has not been studied in the well‐controlled fields.

In this study, the effects of maternal population density on offspring stress axis, reproduction and population dynamics were studied in root voles (Microtus oeconomus). Parental enclosures for breeding offspring were established by introducing six adults per sex into each of 4 (low density) and 30 adults per sex into each of another 4 (high density) enclosures. Live‐trapping started 2 weeks after. Offspring captured at age of 20–30 days were removed to the laboratory, housed under laboratory conditions until puberty, and subsequently used to establish offspring populations in these same enclosures, after parental populations had been removed. [Correction added on 8 January 2015 after first online publication: ‘10–20 days’ has been changed to ‘20–30 days.’] Offspring from each of the two parental sources were assigned into four enclosures with two for each of the two density treatments used in establishing parental populations (referred to as LL and LH for maternally unstressed offspring, assigned in low and highdensity, and HL and HH for maternally stressed offspring, assigned in low and high density). Faecal corticosterone metabolites (FCM) levels, offspring reproduction traits and population dynamics were tested following repeated live‐trapping over two seasons.

Differential fluctuations in population size were observed between maternally density‐stressed and density‐unstressed offspring. Populations in LL and LH groups changed significantly in responding to initial density and reached the similar levels at beginning of the second trapping season. Populations in HL and HH groups, however, were remained relatively steady, and in HL group, the low population size was sustained until end of experiment. Maternal density stress was associated with FCM elevations, reproduction suppression and body mass decrease at sexual maturity in offspring. The FCM elevations and reproduction suppression were independent of offspring population density and correlated with decreased offspring quality.

These findings indicate that intrinsic state alterations induced by maternal stress impair offspring capacity in response to immediate environment, and these alterations are likely mediated by maternal stress system. The maladaptive reproduction suppression seen in HL group suggests intrinsic population density as one of ecological factors generating delayed density‐dependent effects.
Fungal symbiont effects on dune plant diversity depend on precipitation
Authors: Rudgers Jennifer A. , Bell‐Dereske Lukas , Crawford Kerri M. , Emery Sarah M.
Published: October 2014

Historically, mutualisms have been considered to be less important than antagonisms in affecting the composition of ecological communities. In plant communities, beneficial microbes may feature as keystone mutualists in structuring community composition. Understanding the direction and magnitude of mutualist effects at the community scale may be critical for making accurate predictions on plant responses to climate change, particularly for mutualists that ameliorate climate‐induced stressors. Such mitigation could shift outcomes between mutualist‐enhanced species diversity and mutualist‐reduced diversity, depending on whether a mutualist accelerates habitat modification or competitive exclusion by its partner species.

Here, we tested the relative importance and interactive effects of altered precipitation and symbiosis between an epichloid fungal endophyte and a dominant grass species for dune plant communities along the Great Lakes, USA. In 2010, we imposed field manipulations of endophyte presence in the foundation dune grass Ammophila breviligulata in combination with rainout shelters and rainfall additions. We monitored natural rates of colonization by new plant individuals over 3 years.

Under the current precipitation regime, endophyte symbiosis in A. breviligulata reduced colonizing plant diversity, species richness and evenness. This effect depended on the amount of precipitation, with the symbiosis having weaker effects on plant diversity under both augmented and reduced rainfall treatments.

Despite the overall negative effect of endophyte symbiosis on plant diversity, plant responses to the endophyte were species specific. A federally threatened forb, Cirsium pitcheri, increased in abundance when the symbiosis was present, regardless of precipitation regime. Endophyte symbiosis in A. breviligulata caused minor reductions in the abundance of other grass species; however, augmented precipitation benefited other grasses.

Synthesis. We show that microbial mutualisms can have strong effects on community structure in a native ecosystem and that the amount of precipitation has the potential to alter how these keystone species interactions affect community composition. Predictions on future plant community structure, for both restored and native dunes, can be improved by accounting for the presence of fungal symbionts in the foundation plant species.
Types and sequences of self‐regulated reading of low‐achieving adolescents in relation to reading task achievement
Authors: de Milliano Ilona , van Gelderen Amos , Sleegers Peter
Published: October 2014

This study examines the relationship between types and sequences of self‐regulated reading activities in task‐oriented reading with quality of task achievement of 51 low‐achieving adolescents (Grade 8). The study used think aloud combined with video observations to analyse the students' approach of a content‐area reading task in the stages of orientation, text reading and answering questions. Results show that in general these low‐achieving adolescents are infrequently monitoring their text comprehension or making connections with prior knowledge. Nevertheless, important differences are found between types and sequences of self‐regulated reading activities related to task achievement. The low‐achieving adolescents showing a straightforward linear approach to the task (orientation, reading of the whole text and finally answering of questions) yielded more success. In addition, readers demonstrating more activities directed at connections between text contents and prior knowledge during reading showed better task achievement. Implications of these findings for literacy education of this special group of adolescents are discussed.
Salivary interleukin‐17 and tumor necrosis factor‐α in relation to periodontitis and glycemic status in type 2 diabetes mellitus
Authors: Gürsoy Ulvi Kahraman , Yildiz Çiftlikli Sinem , Könönen Eija , Gürsoy Mervi , Doğan Başak
Published: October 2014

Background

Poorly‐controlled glycemic status in type 2 diabetes mellitus (T2DM) is suggested to play a role in the periodontal inflammatory process by aggregating the local cytokine response. Our objectives were to profile salivary interleukin (IL)‐17 and tumor necrosis factor (TNF)‐α levels in subjects with T2DM and to examine their relevance for the periodontal health status and glycemic control levels.

Methods

Unstimulated whole saliva samples, together with full‐mouth periodontal recordings (plaque index [PI], bleeding on probing [BOP %], gingival index [GI], probing pocket depth [PPD], and clinical attachment level [CAL]), were collected from 123 subjects with T2DM. Additionally, demographic and general health parameters, including fasting blood glucose, glycated hemoglobin (HbA1c), were collected. Salivary IL‐17 and TNF‐α concentrations were analyzed using the Luminex®‐xMAP™ technique.

Results

Subjects with poorly‐controlled T2DM (HbA1c ≥ 7) had elevated serum triglyceride (P < 0.001) concentration as well as elevated scores of BOP % (P = 0.014), PI (P = 0.048), GI (P = 0.033), and CAL (P = 0.003) in comparison to those of well‐controlled T2DM (HbA1c < 7). When the subjects with detectable salivary IL‐17 were categorized in tertiles, the scores of PPD and BOP%, and salivary TNF‐α concentrations were significantly elevated in the highest (P = 0.007, P = 0.002 and P < 0.001, respectively) and middle (P = 0.052, P = 0.022, and P = 0.003, respectively) tertiles compared to subjects with non‐detectable salivary IL‐17. The adjusted association between PPD measurements and salivary IL‐17 concentrations was significant (P = 0.008).

Conclusions

Poorly‐controlled glycemic status relates to the severity of periodontal disease in T2DM. The association between PPD and IL‐17 in saliva, however, is independent from the effect of glycemic status.
White coat effect and masked uncontrolled hypertension in treated hypertensive‐diabetic patients: Prevalence and target organ damage
Authors: Leiria Liana F. , Severo Mateus D. , Ledur Priscila S. , Becker Alexandre D. , Aguiar Fernanda M. , Massierer Daniela , Freitas Valéria C. , Schaan Beatriz D. , Gus Miguel
Published: October 2014

Background

The association between hypertensive phenotypes of controlled hypertension (CH), white‐coat effect (WCE), masked uncontrolled hypertension (MUH) and sustained hypertension (SH) with target organ damage have not been clearly established in diabetic hypertensive treated patients. The present study aims to evaluate the prevalence of the four phenotypes considering the current cut‐off points for office and 24 h‐ambulatory blood pressure monitoring (ABPM) and the association with left ventricle hypertrophy (LVH), diastolic function and nephropathy.

Methods

Cross‐sectional study with 304 patients on anti‐hypertensive treatment aged 57.6 ± 6.1 years, who were submitted to ABPM and echocardiography. They were classified into CH (normal office BP and ABPM), WCE (high office BP and normal ABPM), MUH (normal office BP and high ABPM), and SH (high office BP and ABPM).

Results

Median HbA1c and diabetes duration were 7.9% (6.8–9.2), and 10 years (5–16), respectively. Prevalences of CH, WCE, MUH and SH were 27.3%, 17.1%, 18.8%, and 36.8%. MUH prevalence was higher than previously described. There was a significant increasing trend across the four groups in variables related to LVH (P < 0.001 for trend). There was not a clear “dose‐response” relationship of the four hypertensive phenotypes with nephropathy and diastolic function.

Conclusion

The use of ABPM beyond the traditional cardiovascular risk stratification tools has limitations, but is still useful in high‐risk patients. Longitudinal studies could better evaluate the role of the use of ABPM in this scenario. Cut‐off points for normality of office and ABPM influence the prevalences of WCH and MUH.
Pharmacological characterization of ZYDPLA1, a novel long‐acting dipeptidyl peptidase‐4 inhibitor
Authors: Jain Mukul R. , Joharapurkar Amit A. , Bahekar Rajesh H. , Patel Harilal , Jadav Pradip , Kshirsagar Samadhan G. , Patel Vishal J. , Patel Kartikkumar N. , Ramanathan Vikram K. , Patel Pankaj R. , Desai Ranjit C.
Published: October 2014

Objective

Dipeptidyl peptidase‐4 (DPP‐4) is responsible for degradation of glucagon‐like peptide 1 (GLP‐1) and gastric inhibitory polypeptide (GIP), the endogenous incretins that stimulate glucose‐dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP‐4 inhibitor ZYDPLA1.

Methods

In vitro inhibition potency and selectivity were assessed using recombinant enzymes and/or plasma. In vivo efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL/6J mice, db/db mice and Zucker fatty rats. Pharmacokinetics/pharmacodynamics was studied in mice, rats, dogs, and non‐human primates.

Results

ZYDPLA1 is a potent, competitive and long acting inhibitor of DPP‐4 (Ki 0.0027 μM; Koff 2.3 × 10–4 s–1). ZYDPLA1 was more than 7000‐fold selective for recombinant DPP‐4 relative to DPP‐8 and DPP‐9, and more than 60 000‐fold selective relative to fibroblast activation protein (FAP) in vitro. DPP‐4 inhibition was comparable across species. In vivo, oral ZYDPLA1 elevated circulating GLP‐1 and insulin levels in mice and rats and showed dose‐dependent anti‐hyperglycemic effect. Anti‐hyperglycemic effect was also observed in db/db mice and Zucker fatty rats. ZYDPLA1 showed low clearance, large volume of distribution, and a long half‐life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP‐4 activity in mice and rats for more than 48 h, and for up to 168 h in dogs and non‐human primates. Allometric scaling predicted a half‐life in humans of 53 to 166 h.

Conclusion

ZYDPLA1 is a potent, selective, long‐acting oral DPP‐4 inhibitor with potential to become once‐a‐week therapy for treatment of type 2 diabetes mellitus.
Replication levels, false presences and the estimation of the presence/absence from eDNA metabarcoding data
Authors: Ficetola Gentile F. , Pansu Johan , Bonin Aurélie , Coissac Eric , Giguet‐Covex Charline , De Barba Marta , Gielly Ludovic , Lopes Carla M. , Boyer Frédéric , Pompanon François , Rayé Gilles , Taberlet Pierre
Published: October 2014

Environmental DNA (eDNA) metabarcoding is increasingly used to study the present and past biodiversity. eDNA analyses often rely on amplification of very small quantities or degraded DNA. To avoid missing detection of taxa that are actually present (false negatives), multiple extractions and amplifications of the same samples are often performed. However, the level of replication needed for reliable estimates of the presence/absence patterns remains an unaddressed topic. Furthermore, degraded DNA and PCR/sequencing errors might produce false positives. We used simulations and empirical data to evaluate the level of replication required for accurate detection of targeted taxa in different contexts and to assess the performance of methods used to reduce the risk of false detections. Furthermore, we evaluated whether statistical approaches developed to estimate occupancy in the presence of observational errors can successfully estimate true prevalence, detection probability and false‐positive rates. Replications reduced the rate of false negatives; the optimal level of replication was strongly dependent on the detection probability of taxa. Occupancy models successfully estimated true prevalence, detection probability and false‐positive rates, but their performance increased with the number of replicates. At least eight PCR replicates should be performed if detection probability is not high, such as in ancient DNA studies. Multiple DNA extractions from the same sample yielded consistent results; in some cases, collecting multiple samples from the same locality allowed detecting more species. The optimal level of replication for accurate species detection strongly varies among studies and could be explicitly estimated to improve the reliability of results.
Nucleotide variability and gene expression reveal new putative genes related to seed shattering in weedy rice
Authors: Nunes A.L. , Markus C. , Delatorre C.A. , Merotto A.
Published: October 2014

Seed shattering is one of the main traits related with the domestication of cultivated rice and with the invasiveness and persistence of weedy rice. Two independent studies in 2006 have indicated that qSH1 in Japonica and Sh4 in Indica rice are major genes governing this trait. However, a wide variation of seed shattering occurs in weedy rice ecotypes from the same geographic region and even within the same ecotype. The aim of this study was to evaluate the nucleotide variability of known and putative genes related to seed shattering in cultivated rice and to identify and validate new genes related to this trait in weedy rice. The qSH1 gene was not associated with seed shattering in the evaluated genotypes. The nucleotide variability of the genes Os01g0849100 and Os08g0512400, previously identified based on a genome‐wide resequencing study, was related to seed shattering in rice. The nucleotide variability of three single nucleotide polymorphisms (SNPs) of the OsXTH8 gene, which is related to cell wall biosynthesis, was not associated with seed shattering. However, the high expression of this gene was related to the occurrence of this trait. This study evaluated jointly a series of genes involved in rice seed shattering and indicated that the genes OsXTH8, Os08g0512400 and Os01g0849100 are important for the regulation of this trait in weedy rice in addition to previously described genes. Seed shattering in weedy rice has a more complex regulation than in cultivated rice where few major genes were identified.
Prospection and molecular analysis of CpGV isolates infecting Cydia pomonella at different geographical locations in Argentina
Authors: Arneodo J.D. , De Anna J. , Salvador R. , Farinon M. , Quintana G. , Sciocco‐Cap A.
Published: October 2014

The occurrence and genetic diversity of Cydia pomonella granulovirus infecting C. pomonella across Argentina were investigated. Larvae were collected from fruit orchards in regions where CpGV‐based biopesticides have been extensively used and then discontinued (Catamarca) or are still being used (Alto Valle). The survey was also extended to regions where few occasional (i.e. Mendoza) or no virus treatments (various locations) have been made. PCR analysis showed an unexpectedly high proportion of infected larvae (31.3–50%) at most sampling sites in Catamarca. Phylogenetic analysis of these samples, based on gran and lef‐8 genes partial sequences, revealed a previously unreported CpGV variant which could not be assigned to any of the known CpGV genome types and formed a well‐defined new cluster. Instead, samples from Alto Valle were genetically similar to isolate CpGV‐M (the active ingredient in commercial formulations). There, the percentage of infected individuals was considerably lower (1.8–21.9%). The virus was not detected in Mendoza or the other sampling regions. Implications of these results on the epidemiology and current classification of CpGV isolates are discussed.
Differential functional role of purinergic and nitrergic inhibitory cotransmitters in human colonic relaxation
Authors: Mañé N. , Gil V. , Martínez‐Cutillas M. , Clavé P. , Gallego D. , Jiménez M.
Published: October 2014

Aim

ATP and nitric oxide (NO) are released from enteric inhibitory motor neurones and are responsible for colonic smooth muscle relaxation. However, how frequency of neural stimulation affects this cotransmission process and the post‐junctional responses has not been systematically characterized in the human colon.

Methods

The dynamics of inhibitory cotransmission were studied using different protocols of electrical field stimulation (EFS) to characterize the inhibitory junction potentials (IJP) and the corresponding relaxation in colonic strips obtained from 36 patients.

Results

Single pulses elicited a fast IJP (IJPfMAX = −27.6 ± 1.6 mV), sensitive to the P2Y1 antagonist MRS2500 1 μm, that ran down with frequency increase leaving a residual hyperpolarization at high frequencies (IJPf∞ = −3.7 ± 0.6 mV). Accordingly, low frequencies of EFS caused purinergic transient relaxations that cannot be maintained at high frequencies. Addition of the P2Y1 agonist MRS2365 10 μm during the purinergic rundown did not cause any hyperpolarization. Protein kinase C (PKC), a putative P2Y1 desensitizator, was able to reduce the amplitude of the IJPf when activated, but the rundown was not modified by PKC inhibitors. Frequencies higher than 0.60 ± 0.15 Hz were needed to evoke a sustained nitrergic hyperpolarization that progressively increased reaching IJPs∞ = −13 ± 0.4 mV at high frequencies and leading to a sustained inhibition of spontaneous motility.

Conclusion

Changes in frequency of stimulation possibly mimicking neuronal firing will post‐junctionally determine purinergic vs. nitrergic responses underlying different functional roles. NO will be responsible for sustained relaxations needed in physiological processes such as storage, while purinergic neurotransmission evoking sharp transient relaxations will be dominant in processes such as propulsion.
Dynamic changes of the inflammation‐based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study
Authors: Pinato D. J. , Karamanakos G. , Arizumi T. , Adjogatse D. , Kim Y. W. , Stebbing J. , Kudo M. , Jang J. W. , Sharma R.
Published: October 2014

Background

Transarterial chemoembolisation (TACE) is a standard treatment for unresectable, intermediate stage hepatocellular carcinoma (HCC). Survival after TACE, however, can be highly variable, with no suitable biomarker predicting therapeutic outcome. The inflammation‐based index (IBI) has previously been shown to independently predict overall survival (OS) in all stages of HCC.

Aim

To explore the prognostic ability of IBI as a predictor of survival after TACE.

Methods

Baseline staging, biochemical and clinicopathological features including IBI were studied in a derivation set of 64 patients undergoing TACE for intermediate stage HCC. Dynamic changes in IBI before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model and further validated in two independent patient cohorts from Korea (n = 76) and Japan (n = 577).

Results

Pre‐treatment IBI predicted for OS in the derivation set (P = 0.001). Other univariate predictors of OS included radiological response to TACE (P < 0.001), pre‐TACE CLIP score (P < 0.01), tumour diameter >5 cm (P = 0.05) and AFP ≥400 (P < 0.001). Normalisation of IBI post‐TACE was associated with radiological response by mRECIST criteria and improved OS (P < 0.001). Normalisation of IBI remained a significant multivariate predictor of OS in both the derivation and validation sets (P < 0.001).

Conclusions

Normalisation of IBI after TACE is shown to be an independent predictor of survival and may be integrated into the retreatment criteria for repeat TACE in intermediate stage HCC. IBI and its dynamic changes after treatment are validated as a biomarker allowing the stratification of patients with a significant survival advantage following initial TACE.
Social Psychology and the Great Recession: Comment on Bridging the Gap
Authors: Fiske Susan T.
Published: October 2014

Despite appreciating the importance of bridging–or perhaps because of it–we must also appreciate the challenges of any micro‐macro interplay. Many psychological scientists work on social issues precisely because we are frustrated by the untested and often untenable psychological assumptions made by more macro social and economic sciences. At the psychological level of analysis, the array of approaches here to the social psychology of the Great Recession suggests a full agenda. The articles use quite a varied set of methods and forms of inequality, but these do not exhaust the possibilities for future work.
Structured Functional Principal Component Analysis
Authors: Shou Haochang , Zipunnikov Vadim , Crainiceanu Ciprian M. , Greven Sonja
Published: October 2014

Motivated by modern observational studies, we introduce a class of functional models that expand nested and crossed designs. These models account for the natural inheritance of the correlation structures from sampling designs in studies where the fundamental unit is a function or image. Inference is based on functional quadratics and their relationship with the underlying covariance structure of the latent processes. A computationally fast and scalable estimation procedure is developed for high-dimensional data. Methods are used in applications including high-frequency accelerometer data for daily activity, pitch linguistic data for phonetic analysis, and EEG data for studying electrical brain activity during sleep.
Adverse effects of androgen‐deprivation therapy in prostate cancer and their management
Authors: Rhee Handoo , Gunter Jennifer H. , Heathcote Peter , Ho Ken , Stricker Phillip , Corcoran Niall M. , Nelson Colleen C.
Published: October 2014

Objective

To provide an up‐to‐date summary of current literature on the management of adverse effects of androgen‐deprivation therapy (ADT).

Patients and Methods

All relevant medical literature on men with prostate cancer treated with ADT from 2005 to 2014, and older relevant papers, were reviewed. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document.

Results

There are numerous adverse effects of ADT that require pro‐active prevention and treatment. Ranging from cardiovascular disease, diabetes and osteoporosis, to depression, cognitive decline and sexual dysfunction, the range of adverse effects is wide. Baseline assessment, monitoring, prevention and consultation from a multidisciplinary team are important in minimising the harm from ADT.

Conclusions

This review provides a series of practical recommendations to assist with managing the adverse effects of ADT.
Diacylglycerol kinase κ (DGKK) variants and hypospadias in Han Chinese: association and meta‐analysis
Authors: Ma Qichao , Tang Yunman , Lin Houwei , Xu Maosheng , Xu Guofeng , Fang Xiaoliang , Chen Jianhua , Song Zhijian , Li Zhiqiang , Shi Yongyong , Geng Hongquan
Published: October 2014

Objective

To investigate whether diacylglycerol kinase κ (DGKK) is a susceptibility gene for hypospadias in the Han Chinese population as has been suggested by previous publications.

Patients Subjects and Methods

A case‐control study involving 466 patients with hypospadias and 402 healthy subjects was conducted to assess the relationship between DGKK single nucleotide polymorphisms (SNPs) and hypospadias risk in the Han Chinese population. The 466 hypospadias patients were further divided into mild, moderate and severe subgroups for analysis.

Results

Six SNPs (rs1934179, rs4143304, rs9969978, rs1934188, rs4826632 and rs4599945) were marginally associated with mild and moderate hypospadias [odds ratios (ORs) > 1, P = 0.05 to P < 0.1), whereas no significant relationship was seen with the severe cases (ORs >1, P > 0.1). After correcting for multiple testing, it was determined that neither individual SNPs nor individual haplotypes were associated with hypospadias. To evaluate this relationship in multiple populations, we performed a meta‐analysis on six SNPs, using combined data from our present results and those of previous studies of different races (including 1966 patients and 2492 controls). Six SNPs (rs1934179, rs4143304, rs9969978, rs1934188, rs7063116 and rs1934190) were significantly associated with mild/moderate hypospadias (ORs >1, P < 0.05), and rs1934179 was significantly associated with severe hypospadias (OR > 1, P < 0.05).

Conclusions

DGKK gene variants do not appear to play a major role in hypospadias susceptibility in the Chinese Han population. Our meta‐analysis supports the hypothesis that DGKK is a common risk gene for hypospadias, particularly in cases of mild or moderate hypospadias in Caucasian populations.