bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Pol IV/RDR2-dependent transcripts at the genomic scale in Arabidopsis reveals features and regulation of siRNA biogenesis
Authors: Li Shaofang , Vandivier Lee E. , Tu Bin , Gao Lei , Won So Youn , Li Shengben , Zheng Binglian , Gregory Brian D. , Chen Xuemei
Published: November 2014

Twenty-four-nucleotide small interfering (si)RNAs are central players in RNA-directed DNA methylation (RdDM), a process that establishes and maintains DNA methylation at transposable elements to ensure genome stability in plants. The plant-specific RNA polymerase IV (Pol IV) is required for siRNA biogenesis and is believed to transcribe RdDM loci to produce primary transcripts that are converted to double-stranded RNAs (dsRNAs) by RDR2 to serve as siRNA precursors. Yet, no such siRNA precursor transcripts have ever been reported. Here, through genome-wide profiling of RNAs in genotypes that compromise the processing of siRNA precursors, we were able to identify Pol IV/RDR2-dependent transcripts from tens of thousands of loci. We show that Pol IV/RDR2-dependent transcripts correspond to both DNA strands, whereas the RNA polymerase II (Pol II)-dependent transcripts produced upon derepression of the loci are derived primarily from one strand. We also show that Pol IV/RDR2-dependent transcripts have a 5′ monophosphate, lack a poly(A) tail at the 3′ end, and contain no introns; these features distinguish them from Pol II-dependent transcripts. Like Pol II-transcribed genic regions, Pol IV-transcribed regions are flanked by A/T-rich sequences depleted in nucleosomes, which highlights similarities in Pol II- and Pol IV-mediated transcription. Computational analysis of siRNA abundance from various mutants reveals differences in the regulation of siRNA biogenesis at two types of loci that undergo CHH methylation via two different DNA methyltransferases. These findings begin to reveal features of Pol IV/RDR2-mediated transcription at the heart of genome stability in plants.
Structure of a backtracked state reveals conformational changes similar to the state following nucleotide incorporation in human norovirus polymerase
Authors: Zamyatkin Dmitry , Rao Chandni , Hoffarth Elesha , Jurca Gabriela , Rho Hayeong , Parra Francisco , Grochulski Pawel , Ng Kenneth Kai-Sing
Published: November 2014

The RNA-dependent RNA polymerase (RdRP) from norovirus (NV) genogroup II has previously been crystallized as an apoenzyme (APO1) in multiple crystal forms, as well as as a pre-incorporation ternary complex (PRE1) bound to Mn2+, various nucleoside triphosphates and an RNA primer-template duplex in an orthorhombic crystal form. When crystallized under near-identical conditions with a slightly different RNA primer/template duplex, however, the enzyme–RNA complex forms tetragonal crystals (anisotropic data,dmin≃ 1.9 Å) containing a complex with the primer/template bound in a backtracked state (BACK1) similar to a post-incorporation complex (POST1) in a step of the enzymatic cycle immediately following nucleotidyl transfer. The BACK1 conformation shows that the terminal nucleotide of the primer binds in a manner similar to the nucleoside triphosphate seen in the PRE1 complex, even though the terminal two phosphoryl groups in the triphosphate moiety are absent and a covalent bond is present between the α-phosphoryl group of the terminal nucleotide and the 3′-oxygen of the penultimate nucleotide residue. The two manganese ions bound at the active site coordinate to conserved Asp residues and the bridging phosphoryl group of the terminal nucleotide. Surprisingly, the conformation of the thumb domain in BACK1 resembles the open APO1 state more than the closed conformation seen in PRE1. The BACK1 complex thus reveals a hybrid state in which the active site is closed while the thumb domain is open. Comparison of the APO1, PRE1 and BACK1 structures of NV polymerase helps to reveal a more complete and complex pathway of conformational changes within a single RdRP enzyme system. These conformational changes lend insight into the mechanism of RNA translocation following nucleotidyl transfer and suggest novel approaches for the development of antiviral inhibitors.
Structures of an Eph receptor tyrosine kinase and its potential activation mechanism
Authors: Wei Qiang , Liu Jun , Wang Nan , Zhang Xiaoying , Jin Jin , Chin-Sang Ian , Zheng Jimin , Jia Zongchao
Published: November 2014

Eph receptor tyrosine kinases (RTKs) and their ephrin ligands play a crucial role in both physiological and pathophysiological processes, including tumourigenesis. A previous study of Eph RTKs established a regulatory role for the juxtamembrane segment (JMS) in kinase activation through the phosphorylation of two tyrosines within the JMS. Here, structures of EphA2 representing various activation states are presented. By determining the unphosphorylated inactive and phosphorylated active structures as well as an alternative conformation, conformational changes during kinase activation have been revealed. It is shown that phosphorylation of a tyrosine residue (Tyr772) in the activation loop without direct involvement of the JMS is sufficient to activate the EphA2 kinase. This mechanistic finding is in contrast to the mechanism of other Eph RTKs, such as EphB2, in which phosphorylation of the two JMS tyrosines initiates the dissociation of the JMS and triggers activation-loop phosphorylation for kinase activation. Furthermore, experiments demonstrate that the EphA2 substrate PTEN, a phosphatase that has been implicated in tumour suppression, acts to regulate the phosphorylation states of EphA2, exemplifying a unique reciprocal enzyme–substrate system. Based on these studies, it is therefore suggested that EphA2 may possess an alternate activation mechanism distinct from other Eph RTKs.
Structures of trehalose synthase fromDeinococcus radioduransreveal that a closed conformation is involved in catalysis of the intramolecular isomerization
Authors: Wang Yung-Lin , Chow Sih-Yao , Lin Yi-Ting , Hsieh Yu-Chiao , Lee Guan-Chiun , Liaw Shwu-Huey
Published: November 2014

Trehalose synthase catalyzes the simple conversion of the inexpensive maltose into trehalose with a side reaction of hydrolysis. Here, the crystal structures of the wild type and the N253A mutant ofDeinococcus radioduranstrehalose synthase (DrTS) in complex with the inhibitor Tris are reported. DrTS consists of a catalytic (β/α)8barrel, subdomain B, a C-terminal β domain and two TS-unique subdomains (S7 and S8). The C-terminal domain and S8 contribute the majority of the dimeric interface. DrTS shares high structural homology with sucrose hydrolase, amylosucrase and sucrose isomerase in complex with sucrose, in particular a virtually identical active-site architecture and a similar substrate-induced rotation of subdomain B. The inhibitor Tris was bound and mimics a sugar at the −1 subsite. A maltose was modelled into the active site, and subsequent mutational analysis suggested that Tyr213, Glu320 and Glu324 are essential within the +1 subsite for the TS activity. In addition, the interaction networks between subdomains B and S7 seal the active-site entrance. Disruption of such networks through the replacement of Arg148 and Asn253 with alanine resulted in a decrease in isomerase activity by 8–9-fold and an increased hydrolase activity by 1.5–1.8-fold. The N253A structure showed a small pore created for water entry. Therefore, our DrTS-Tris may represent a substrate-induced closed conformation that will facilitate intramolecular isomerization and minimize disaccharide hydrolysis.
Structural implications of the C-terminal tail in the catalytic and stability properties of manganese peroxidases from ligninolytic fungi
Authors: Fernández-Fueyo Elena , Acebes Sandra , Ruiz-Dueñas Francisco J. , Martínez María Jesús , Romero Antonio , Medrano Francisco Javier , Guallar Victor , Martínez Angel T.
Published: November 2014

The genome ofCeriporiopsis subvermisporaincludes 13 manganese peroxidase (MnP) genes representative of the three subfamilies described in ligninolytic fungi, which share an Mn2+-oxidation site and have varying lengths of the C-terminal tail. Short, long and extralong MnPs were heterologously expressed and biochemically characterized, and the first structure of an extralong MnP was solved. Its C-terminal tail surrounds the haem-propionate access channel, contributing to Mn2+oxidation by the internal propionate, but prevents the oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), which is only oxidized by short MnPs and by shortened-tail variants from site-directed mutagenesis. The tail, which is anchored by numerous contacts, not only affects the catalytic properties of long/extralong MnPs but is also associated with their high acidic stability. Cd2+binds at the Mn2+-oxidation site and competitively inhibits oxidation of both Mn2+and ABTS. Moreover, mutations blocking the haem-propionate channel prevent substrate oxidation. This agrees with molecular simulations that position ABTS at an electron-transfer distance from the haem propionates of anin silicoshortened-tail form, while it cannot reach this position in the extralong MnP crystal structure. Only small differences exist between the long and the extralong MnPs, which do not justify their classification as two different subfamilies, but they significantly differ from the short MnPs, with the presence/absence of the C-terminal tail extension being implicated in these differences.
The crystal structure of human mitochondrial 3-ketoacyl-CoA thiolase (T1): insight into the reaction mechanism of its thiolase and thioesterase activities
Authors: Kiema Tiila-Riikka , Harijan Rajesh K. , Strozyk Malgorzata , Fukao Toshiyuki , Alexson Stefan E. H. , Wierenga Rik K.
Published: November 2014

Crystal structures of human mitochondrial 3-ketoacyl-CoA thiolase (hT1) in the apo form and in complex with CoA have been determined at 2.0 Å resolution. The structures confirm the tetrameric quaternary structure of this degradative thiolase. The active site is surprisingly similar to the active site of theZoogloea ramigerabiosynthetic tetrameric thiolase (PDB entries 1dm3 and 1m1o) and different from the active site of the peroxisomal dimeric degradative thiolase (PDB entries 1afw and 2iik). A cavity analysis suggests a mode of binding for the fatty-acyl tail in a tunnel lined by the Nβ2–Nα2 loop of the adjacent subunit and the Lα1 helix of the loop domain. Soaking of the apo hT1 crystals with octanoyl-CoA resulted in a crystal structure in complex with CoA owing to the intrinsic acyl-CoA thioesterase activity of hT1. Solution studies confirm that hT1 has low acyl-CoA thioesterase activity for fatty acyl-CoA substrates. The fastest rate is observed for the hydrolysis of butyryl-CoA. It is also shown that T1 has significant biosynthetic thiolase activity, which is predicted to be of physiological importance.
The structural basis of the Tle4–Tli4 complex reveals the self-protection mechanism of H2-T6SS inPseudomonas aeruginosa
Authors: Lu Defen , Zheng Youshi , Liao Naishun , Wei Ling , Xu Bo , Liu Xiaolong , Liu Jingfeng
Published: November 2014

The type VI secretion system (T6SS) has recently been demonstrated to mediate interbacterial competition and to discriminate between self and nonself. T6SS+bacteria employ toxic effectors to inhibit rival cells and concurrently use effector cognate immunity proteins to protect their sibling cells. The effector and immunity pairs (E–I pairs) endow the bacteria with a great advantage in niche competition. Tle4–Tli4 (PA1510–PA1509) is a newly identified E–I pair that is controlled by H2-T6SS inPseudomonas aeruginosa. Tle4 exhibits phospholipase activity, which destroys the cell membrane of rival cells, and the periplasm-located Tli4 in donor cells eliminates this toxic effect of Tle4. In this paper, the structure of the Tle4–Tli4 complex is reported at 1.75 Å resolution. Tle4 consists of two domains: a conserved α/β-hydrolase domain and an unusual cap domain in which two lid regions (lid1 and lid2) display a closed conformation that buries the catalytic triad in a deep funnel. Tli4 also displays a two-domain structure, in which a large lobe and a small lobe form a crab claw-like conformation. Tli4 uses this crab claw to grasp the cap domain of Tle4, especially the lid2 region, which prevents the interfacial activation of Tle4 and thus causes enzymatic dysfunction of Tle4 in sister cells.
A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway
Authors: Pavlovsky Alexander G. , Thangavelu Bharani , Bhansali Pravin , Viola Ronald E.
Published: November 2014

The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate β-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme–inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors.
Crystal structure of di-μ-iodido-bis[(dimethyl sulfoxide-κO)(triphenylphosphane-κP)copper(I)]
Authors: Kinghat Rodolphe , Knorr Michael , Rousselin Yoann , Kubicki Marek M.
Published: November 2014

The centrosymmetric dinuclear title compound, [Cu2I2(C2H6OS)2(C18H15P)2], represents the first example of a CuI complex ligated by anO-bound dimethyl sulfoxide ligand. In the crystal, the two tetrahedrally coordinated CuIatoms are bridged by two μ2-iodido ligands in an almost symmetrical rhomboid geometry. The loose Cu...Cu contact of 2.9874 (8) Å is longer than the sum of the van der Waals radii of two Cu atoms (2.8 Å), excluding a significant cupriophilic interaction in the actual dimer. C—H...O and C—H...I hydrogen bonding interactions as well as C—H...π(aryl) interactions stabilize the three-dimensional supramolecular network.
Crystal structure of 1-methyl-4-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine
Authors: El Fal Mohammed , Ramli Youssef , Essassi El Mokhtar , Saadi Mohamed , El Ammari Lahcen
Published: November 2014

In the title compound, C7H8N4S, the non-H atoms of the pyrazolo[3,4-d]pyrimidine ring system and the methylsulfanyl group lie on a crystallographic mirror plane. In the crystal, molecules are linkedviaa number of π–π interactions [centroid–centroid distances vary from 3.452 (7) to 3.6062 (8) Å], forming a three-dimensional structure.
Crystal structures of three lead(II) acetate-bridged diaminobenzene coordination polymers
Authors: Geiger David K. , Parsons Dylan E. , Zick Patricia L.
Published: November 2014

Poly[tris(acetato-κ2O,O′)(μ2-acetato-κ3O,O′:O)tetrakis(μ3-acetato-κ4O,O′:O:O′)bis(benzene-1,2-diamine-κN)tetralead(II)], [Pb4(CH3COO)8(C6H8N2)2]n, (I), poly[(acetato-κ2O,O′)(μ3-acetato-κ4O,O′:O:O′)(4-chlorobenzene-1,2-diamine-κN)lead(II)], [Pb(CH3COO)2(C6H7ClN2)]n, (II), and poly[(κ2O,O′)(μ3-acetato-κ4O,O′:O:O′)(3,4-diaminobenzonitrile-κN)lead(II)], [Pb(CH3COO)2(C7H7N3)]n, (III), have polymeric structures in which monomeric units are joined by bridging acetate ligands. All of the PbIIions exhibit hemidirected coordination. The repeating unit in (I) is composed of four PbIIions having O6, O6N, O7and O6N coordination spheres, respectively, where N represents a monodentate benzene-1,2-diamine ligand and O acetate O atoms. Chains along [010] are joined by bridging acetate ligands to form planes parallel to (10-1). (II) and (III) are isotypic and have one PbIIion in the asymmetric unit that has an O6N coordination sphere. Pb2O2units result from a symmetry-imposed inversion center. Polymeric chains parallel to [100] exhibit hydrogen bonding between the amine and acetate ligands. In (III), additional hydrogen bonds between cyano groups and non-coordinating amines join the chains by formingR22(14) rings.
Team interdependence and turnover: evidence from the NFL
Authors: L. Davis Justin , Fodor Andy , E. Pfahl Michael , Stoner Jason
Published: November 2014

Purpose

– The purpose of this paper is to empirically investigate the interactive effect of turnover and task interdependence on performance in work teams. Based on pervious research, the authors contend that turnover will have a negative effect on team performance and this effect will be more pronounced as teams perform highly interdependent tasks.

Design/methodology/approach

– Using longitudinal data from the National Football League (NFL), the authors empirically examine the effect of player turnover on NFL team performance (i.e. wins and losses in the subsequent year), and the difference in team performance based on the high/low task interdependence of the work team.

Findings

– Findings suggest a negative impact of turnover on organizational performance, regardless of the interdependent nature of work team tasks. In addition, the negative influence of turnover is enhanced by the task interdependence within a team.

Originality/value

– This is one of the few studies that examine task interdependence as a moderating variable of the turnover – team performance relationship. More specifically, by examining an industry with high team member turnover (i.e. The NFL), the findings from this study give practicing managers a guide as to which work teams managers should attempt to minimize turnover.
Followers’ reactions to self-serving leaders: the influence of the organization's budget policy
Authors: Decoster Stijn , Stouten Jeroen , M. Tripp Thomas
Published: November 2014

Purpose

– Even though leaders often are seen as responsible guides, they sometimes behave in a self-serving way, for example, by spending the company's budget on their own, frivolous needs. In this study, the authors explore an aspect of such behavior: the authors examine how an organizational budget policy makes such spending more legitimate in the eyes of followers. Specifically, the authors examine when followers will react to a leader's self-serving behavior as a function of: the role of organizational budget policies, and whether followers are directly affected by the leader's behavior. The authors test two particular budget policies, i.e. carry-forward vs non-carry-forward (a.k.a., “use-it-or-lose-it” budget policies), which differ on whether a department/team's allocations not spent by the end of the fiscal year flow back to the central administration. The paper aims to discuss these issues.

Design/methodology/approach

– Study 1 is a multi-source field study that should enhance the external validity of the results. Study 1 was analyzed with regression analyses and bootstrapping techniques. To be able to draw causal inferences, the authors also conducted an experimental study (Study 2).

Findings

– Followers react more negatively – by showing increased turnover intentions and decreased commitment and cooperation – to a leader's self-serving behavior in a carry-forward policy than in a use-it-or-lose-it budget policy. Thus, organizational policies, such as the budget policy, affect how followers react to self-serving leaders.

Originality/value

– The authors focus on self-serving leader behavior. The authors show that followers’ reactions to self-serving leaders are not necessarily negative and are influenced by the specific organizational context in which the self-serving behavior occurs. More specifically, the authors add to the literature by introducing budget policies as influencing followers’ reactions to leaders’ behavior.
Significance of lymphovascular invasion in organ‐confined, node‐negative urothelial cancer of the bladder: data from the prospective p53‐MVAC trial
Authors: von Rundstedt Friedrich‐Carl , Mata Douglas A. , Groshen Susan , Stein John P. , Skinner Donald G. , Stadler Walter M. , Cote Richard J. , Kryvenko Oleksandr N. , Godoy Guilherme , Lerner Seth P.
Published: November 2014

Objectives

To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ‐confined, node‐negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI.

Patients and Methods

Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1–T2 N0 UCB in the p53‐MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS).

Results

Among 499 patients with a median follow‐up of 4.9 years, a subset of 102 (20%) had LVI‐positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15–2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31–3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI‐positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16–3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11–1.83; EV 9; P = 0.26).

Conclusions

Our post hoc analysis of the p53‐MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1–T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.
Water immersion colonoscopy facilitates straight passage of the colonoscope through the sigmoid colon without loop formation: Randomized controlled trial
Authors: Asai Satoshi , Fujimoto Naoki , Tanoue Koujirou , Akamine Eisuke , Nakao Eisuke , Hashimoto Kirie , Ichinona Takumi , Nambara Mikio , Sassa Seitarou , Yanagi Hideo , Hirooka Norifumi , Mori Takuji , Ogawa Minoru , Ogawa Atsuhiro
Published: November 2014

Background and Aim

One of the major causes of pain during colonoscopy is looping of the instrument during insertion through the sigmoid colon, which causes discomfort by stretching the mesentery. There are many studies in colonoscope techniques, but they have not been assessed objectively with respect to colonoscope passage through the sigmoid colon without loop formation. The aim of the present study was to determine whether cap‐fitted colonoscopy and water immersion increase the success rate of insertion through the sigmoid without loop formation.

Methods

A total of 1005 patients were randomized to standard colonoscopy, cap‐fitted colonoscopy or water immersion technique. All examinations were carried out under a magnetic endoscope imaging device. Main outcome was the success rate of insertion without loop formation.

Results

Success rate of insertion without loop formation was 37.5%, 40.0%, and 53.8% in the standard, cap, and water groups, respectively (standard vs water P = 0.00014, cap vs water P = 0.00186). There were no significant differences among the groups regarding cecal intubation rate, cecal intubation time and number of polyps ≥5 mm per patient.

Conclusions

Water immersion increases the success rate of insertion through the sigmoid colon without loop formation. This practical technique, requiring only preparation of a cap and water, is useful without compromising cecal intubation rate, cecal intubation time, or polyp detection rate.
The relationship between trunk control in sitting and during gait in children and adolescents with cerebral palsy
Authors: Sæther Rannei , Helbostad Jorunn L , Adde Lars , Brændvik Siri , Lydersen Stian , Vik Torstein
Published: November 2014

Aim

To assess the relationship between trunk control in sitting and trunk control during gait in children and adolescents with cerebral palsy (CP).

Method

Twenty‐six children (17 males, nine females) with spastic CP (Gross Motor Function Classification System I–III [15 unilateral, 11 bilateral], mean age 13.5y), were included. Trunk control in sitting was assessed with the Trunk Impairment Scale (TIS) and the Trunk Control Measurement Scale (TCMS), and trunk control during gait by a trunk‐worn accelerometer. The Pearson's rank correlation coefficient, partial correlation (rp), and linear regression analysis were applied to assess the relationship between trunk control in sitting and during gait.

Results

Trunk control in sitting assessed with the TCMS and the TIS total scores both correlated with trunk accelerations during gait (rp=0.67 and 0.60 respectively). Moreover, some subscale scores correlated equally well with trunk control during gait (the TCMS dynamic sitting balance‐reaching subscale score [DSB‐R]; rp=0.61) or even higher (TIS dynamic sitting balance subscale [DSB]; rp=0.66).

Interpretation

Trunk control in sitting has a moderate to good correlation with trunk control during gait. Our results suggest that the subscale DSB‐R of the TCMS, being less time consuming, may be applied in clinical assessment to gain information on trunk control during gait. Future studies are needed to explore how this information may be applied in the planning of ‘gait interventions’.
He Who Counts Elects: Economic Elites, Political Elites, and Electoral Fraud
Authors: Chaves Isaías , Fergusson Leopoldo , Robinson James A.
Published: November 2014

What determines the extent of electoral fraud? This paper constructs a model of the tradeoff between fraud and policy concessions (public good provision) which also incorporates the strength of the state. In addition, we parameterize the extent to which economic elites (to whom fraud is costly) and political elites (to whom fraud is advantageous) “overlap.” The model predicts that fraud will be lower and public good provision higher when land inequality is higher, the overlap between elites lower, and the strength of the state higher. We test these predictions using a unique, municipal‐level dataset from Colombia's 1922 Presidential elections. We find empirical support for all the predictions of the model.
Multicolinearity and Indicator Redundancy Problem in World University Rankings: An Example Using Times Higher Education World University Ranking 2013–2014 Data
Authors: Kaycheng Soh
Published: November 2014

World university ranking systems used the weight‐and‐sum approach to combined indicator scores into overall scores on which the universities are then ranked. This approach assumes that the indicators all independently contribute to the overall score in the specified proportions. In reality, this assumption is doubtful as the indicators tend to correlate with one another and some highly so. This causes the multicolinearity problem rending some predictors redundant. At the same time, some indicators may contribute so little to the overall score and thus making them non‐contributing. When overlapping and non‐contributing indicators are retained, the overall score takes on a meaning very different from what it is originally intended to be. Using data for the top 101 universities of the Times Higher Education World University Ranking 2013–2014, these problems are demonstrated and a solution is suggested. This resulted in a new overall scores made up of only two of the six indicators, namely ‘research’ and ‘citation’. The universities were then ranked on the basis of the new overall score and compared with the original. It was also noticed that some of the universities have had their original overall scores inflated by the non‐contributing indicators and hence were over‐ranked. Implications for using the new overall and ranking are discussed.
Exploring the Concept of Empire in Pacific History: Individuals, Nations, and Ocean Space Prior to 1850
Authors: Igler David
Published: November 2014

The concept of empire pervades most scholarly discussions of transnational and world history, especially for the 18th and 19th centuries. However, empire as an analytical tool has its limitations for explaining the attitudes and behaviors of individuals in the early modern Pacific Ocean. Drawing on recent scholarship by scholars of the United States, Pacific, and world history, this essay highlights the individualistic activities and motivations of American traders and sailors as they sought profit in the Pacific borderlands prior to 1850.
An Introduction to the Environmental History of the Mamlūk Sultanate
Authors: Frenkel Yehoshua
Published: November 2014

Environmental history, the study of the interaction of nature and society, is a research field that has only recently been applied to Mamlūk studies. It seeks to elucidate all aspects of relations between humans and their physical surroundings: agriculture, subsistence and water management, as well as the discourse about nature and coping of governors and communities with ecological hazards and catastrophes. Since it is anachronistic to use national unites and contemporary borders, this approach is particularly suitable to the study of pre‐modern states, lands and societies, like the Mamlūk Bilād al‐Shām. This paper aims first to map the field and the present state of the art. Its second goal is to delineate potential working theses and research topics that would guide further environmental studies. These investigations would bolster the study of history of rural and urban communities in the east Mediterranean and Near Eastern zone during a quarter of a millennium (1250–1517).
Effects of Flexion and Extension on the Diameter of the Caudal Cervical Vertebral Canal in Dogs
Authors: Ramos Renato M. , da Costa Ronaldo C. , Oliveira Andre L. A. , Kodigudla Manoj K. , Goel Vijay K.
Published: November 2014

Objective

To quantify changes in the diameter of the vertebral canal with flexion and extension in the cervical vertebral column.

Study Design

Cadaveric biomechanical study.

Sample Population

Cadaveric canine cervical vertebral column (n = 16 dogs).

Methods

All vertebral columns were evaluated with MRI. Group 1 consisted of 8 normal vertebral columns. Group 2 included 8 vertebral columns with intervertebral disc degeneration. Flexion, extension, compression, and tension were applied to the caudal cervical region (C4–5, C5–6, C6–7). Sagittal vertebral canal diameters (VCD) were obtained by measuring the distance between the ventral and dorsal aspects of vertebral canal.

Results

No differences were seen between groups, thus the results are for both groups. Comparison of VCD between flexion and extension with no load revealed a difference of 2.2 mm (28.9%;P < .001). Comparison between neutral position and extension revealed a reduction of 1.5 mm (16.5%;P < .001), whereas comparison between neutral and flexion showed an increase of 0.7 mm (7.7%;P = .001) in VCD. Comparison between neutral with no load and neutral with compression showed a difference of 0.5 mm, with reduction of 5.5% in the vertebral canal (P = .006). Comparison of extension with no load versus extension with tension revealed an increase of 0.7 mm (9.2%) in the vertebral canal (P < .001).

Conclusions

Cervical vertebral canal diameter decreased significantly with extension and increased with flexion. The results support the presence of dynamic impingement possibly playing a role in diseases characterized by vertebral canal stenosis, such as cervical spondylomyelopathy.
Convergence of National Innovation Policy Mixes in Europe – Has It Gone Too Far? An Analysis of Research and Innovation Policy Measures in the Period 2004–12
Authors: Izsak Kincsö , Markianidou Paresa , Radošević Slavo
Published: November 2014

A national innovation policy mix comprises the measures that address the innovation policy challenges of the country in question. The data series of the Erawatch and INNO Policy TrendChart initiatives of the European Commission provide a unique opportunity to explore the profiles of the national innovation policy mixes and their evolution during the past decade. In this article, the innovation policy mix per country and changes in these mixes over time are identified. The analysis covers five main policy mix profiles of the EU Member States. An unexpected similarity and stability is found in the national innovation policy mixes of the Member States even though these countries face different innovation challenges. This reflects extensive transnational policy learning, which is a welcome development, but such a similarity among heterogeneous countries might indicate that innovation policies are not being tailored effectively to the real needs and situations in each Member State.
A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy
Authors: Haneda Masakazu , Utsunomiya Kazunori , Koya Daisuke , Babazono Tetsuya , Moriya Tatsumi , Makino Hirofumi , Kimura Kenjiro , Suzuki Yoshiki , Wada Takashi , Ogawa Susumu , Inaba Masaaki , Kanno Yoshihiko , Shigematsu Takashi , Masakane Ikuto , Tsuchiya Ken , Honda Keiko , Ichikawa Kazuko , Shide Kenichiro ,   Joint Committee on Diabetic Nephropathy
Published: November 2014

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m2, regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non‐diabetic kidney disease as being crucial in all stages of diabetic nephropathy.
Association between adaptive behaviour and age in adults with Down syndrome without dementia: examining the range and severity of adaptive behaviour problems
Authors: Makary A. T. , Testa R. , Tonge B. J. , Einfeld S. L. , Mohr C. , Gray K. M.
Published: November 2014

Background

Studies on adaptive behaviour and ageing in adults with Down syndrome (DS) (without dementia) have typically analysed age‐related change in terms of the total item scores on questionnaires. This research extends the literature by investigating whether the age‐related changes in adaptive abilities could be differentially attributed to changes in the number or severity (intensity) of behavioural questionnaire items endorsed.

Methods

The Adaptive Behaviour Assessment System‐II Adult (ABAS‐II Adult) was completed by parents and caregivers of 53 adults with DS aged between 16 and 56 years. Twenty adults with DS and their parents/caregivers were a part of a longitudinal study, which provided two time points of data. In addition 33 adults with DS and their parents/caregivers from a cross‐sectional study were included. Random effects regression analyses were used to examine the patterns in item scores associated with ageing.

Results

Increasing age was found to be significantly associated with lower adaptive behaviour abilities for all the adaptive behaviour composite scores, expect for the practical composite. These associations were entirely related to fewer ABAS‐II Adult items being selected as present for the older participants, as opposed to the scores being attributable to lower item severity.

Conclusions

This study provides evidence for a differential pattern of age‐related change for various adaptive behaviour skills in terms of range, but not severity. Possible reasons for this pattern will be discussed. Overall, these findings suggest that adults with DS may benefit from additional support in terms of their social and conceptual abilities as they age.
Acute hepatitis C infection in HIV‐negative men who have sex with men
Authors: McFaul K. , Maghlaoui A. , Nzuruba M. , Farnworth S. , Foxton M. , Anderson M. , Nelson M. , Devitt E.
Published: November 2014

Acute hepatitis C infection is recognized in HIV‐infected men who have sex with men (MSM), but the risk in HIV‐negative MSM remains unclear. We evaluated a population of MSM with acute hepatitis C. From January 2010 to May 2014, all cases of HCV antibody positive HIV‐negative MSM were identified. European AIDS Network criteria were applied to determine acute infection, and 44 individuals fulfilled the criteria for acute hepatitis C. Ten were RNA negative at baseline and classed as prior spontaneous clearance. 15 (34.1%) had a previously negative HCV antibody within 1 year. 11 (25.0%) had significant elevation in ALT levels, and 18 (40.9%) were clinically diagnosed from risk exposure and history. Median age was 37 years (range 24–75). 41 (93.2%) individuals reported unprotected anal sex, 36 with (87.8%) both insertive and receptive intercourse, 4 (9.8%) with receptive intercourse, 1 (2.4%) with insertive intercourse, and no data were recorded for 3 (7.3%) patients. Individuals had an average of 7.3 reported (median 2, range 1–100) partners. 12 (27.3%) engaged in group sex, 11 (25.0%) practised fisting, 11 (25.0%) admitted using drugs during sexual activity, 16 (36.4%) reported nasal, and 9 (20.5%) reported injection drug use. 14 (31.8)% had unprotected sex whilst under the influence of recreational drugs. 29 individuals were aware of a partner's status. 2 (4.5%) individuals had sexual contact with a known HCV monoinfected partner, 13 (29.5%) with a HIV monoinfected partner and 6 (13.6%) with a HCV/HIV coinfected partner. 9 (20.5%) reported a partner/partners with no known infection. No data were available in 14 (31.8%) individuals. 13 (29.5%) individuals had a coexisting STI at the time of acute HCV diagnosis. 8 (18.2%) received HIV postexposure prophylaxis (PEP) within the 6 months prior to the HCV diagnosis (2 were participants in a HIV pre‐exposure prophylaxis trial). 15 (34.1%) individuals achieved spontaneous clearance of HCV, and 11 patients received HCV treatment. Similar to the ongoing epidemic of acute HCV infection in HIV+ MSM, HIV‐negative MSM remain at risk.
Pharmacokinetics, pharmacodynamics, toxicology and therapeutics of mavacoxib in the dog: a review
Authors: Lees P. , Pelligand L. , Elliott J. , Toutain P.‐L. , Michels G. , Stegemann M.
Published: November 2014

Mavacoxib is a novel nonsteroidal anti‐inflammatory drug (NSAID), with a preferential action on the cyclooxygenase (COX)‐2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic (PK) profile comprises very slow body clearance, long elimination half‐life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis (OA). In OA dogs, mavacoxib exhibits a much longer terminal half‐life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics (PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX‐1 and COX‐2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies.
Effect of enforced physical inactivity induced by 60‐day of bed rest on hepatic markers of NAFLD in healthy normal‐weight women
Authors: Rudwill Floriane , Bergouignan Audrey , Gastebois Caroline , Gauquelin‐Koch Guillemette , Lefai Etienne , Blanc Stéphane , Simon Chantal
Published: November 2014

Background & Aims

Physical inactivity leads to a cluster of metabolic disorders that have been associated with non‐alcoholic fatty liver diseases. We tested whether physical inactivity increases hepatic biomarkers of NAFLDs.

Methods

Sixteen normal‐weight healthy women (body mass index = 21.2 ± 0.5 kg/m2) were studied under controlled energy balance conditions during a previous 60‐day bed rest with (n = 8) or without (n = 8) a combined aerobic/resistive exercise protocol. Stored samples were retrospectively used to measure plasma hepatic markers, i.e. steatosis‐related alanine and aspartate transaminases, cytokeratin 18 and angiopoietin‐like 3, at baseline, after 30 and 60 days of bed rest. Fasting insulin and triglycerides were measured at baseline and after 30 days of bed rest. Two indexes were calculated, one combining alanine and aspartate transaminase and cytokeratin 18 and another cytokeratin 18, homeostasis model assessment of insulin resistance and aspartate aminotransferase.

Results

Sixty days of bed rest increased all hepatic markers (P < 0.05 for all) and the two indexes (P < 0.01 for both). Exercise significantly reduced the elevation in aspartate transaminase, cytokeratin 18 and both indexes (P < 0.02 for all) but not the increase in alanine transaminase and angiopoietin‐like 3. Changes between baseline and 30 days of bed rest in triglycerides were positively associated with changes in aspartate transaminase (R2 = 0.28, P = 0.04) suggesting a role of hypertriglyceridaemia in the alteration of liver metabolism under inactive conditions.

Conclusion

Physical inactivity increases, independent of fat mass, hepatic markers of steatosis and steatohepatitis. Regular exercise can limit these physical inactivity‐induced metabolic alterations. Future studies need to elucidate the underlying mechanisms.
Differential evolution of members of the rhomboid gene family with conservative and divergent patterns
Authors: Li Qi , Zhang Ning , Zhang Liangsheng , Ma Hong
Published: November 2014

Rhomboid proteins are intramembrane serine proteases that are involved in a plethora of biological functions, but the evolutionary history of the rhomboid gene family is not clear.

We performed a comprehensive molecular evolutionary analysis of the rhomboid gene family and also investigated the organization and sequence features of plant rhomboids in different subfamilies.

Our results showed that eukaryotic rhomboids could be divided into five subfamilies (RhoA–RhoD and PARL). Most orthology groups appeared to be conserved only as single or low‐copy genes in all lineages in RhoB–RhoD and PARL, whereas RhoA genes underwent several duplication events, resulting in multiple gene copies. These duplication events were due to whole genome duplications in plants and animals and the duplicates might have experienced functional divergence. We also identified a novel group of plant rhomboid (RhoB1) that might have lost their enzymatic activity; their existence suggests that they might have evolved new mechanisms.

Plant and animal rhomboids have similar evolutionary patterns. In addition, there are mutations affecting key active sites in RBL8, RBL9 and one of the Brassicaceae PARL duplicates. This study delineates a possible evolutionary scheme for intramembrane proteins and illustrates distinct fates and a mechanism of evolution of gene duplicates.
Diagnostic frameworks and nursing diagnoses: a normative stance
Authors: Zanotti Renzo , Chiffi Daniele
Published: November 2014

Diagnostic frameworks are essential to many scientific and technological activities and clinical practice. This study examines the main fundamental aspects of such frameworks. The three components required for all diagnoses are identified and examined, i.e. their normative dimension, temporal nature and structure, and teleological perspective.

The normative dimension of a diagnosis is based on (1) epistemic values when associated with Hempel's inductive risk concerning the balance between false‐positive and false‐negative outcomes, leading to probabilistic judgements; and (2) non‐epistemic values when related to ideas such as well‐being, normality, illness, etc, as idealized norms or ideal points of reference.

It should be noted that medical diagnoses match the three necessary components, while some essential diagnostic frameworks – the taxonomies ofGordon andNANDA– in nursing lack some components. The main lack is normative as the most popular frameworks in nursing diagnosis seem to be descriptions of observed reality rather than normative and value‐based judgements in which both epistemic and non‐epistemic values may coexist.
Modern dying: from securing rights to meeting needs
Authors: Solomon Mildred Z.
Published: November 2014

Modern medicine has transformed the dying experience. In the developed world, most of us no longer die from infectious diseases and sudden accidents, but from chronic illnesses that progressively worsen. Yet the U.S. healthcare system is not designed to meet the needs of people with chronic illness or of frail elders. In addition, our system incentivizes the use of technologies that are often helpful when an underlying condition is reversible but, when used very near the end of life, may only postpone the dying process and increase burdens on the patient. This state of affairs renders many people near the end of life without adequate symptom control, little or no social and psychological support, and inadequate involvement in decisions about when and how best to use modern technologies. This paper traces efforts over the last three decades to address problems related to modern dying. The author sees three phases: early work focused on securing patients’ rights to refuse unwanted treatments, the next phase focused on building the specialty of palliative medicine, and the third and future phase must redesign our healthcare system to better align with how we die in the 21st century.