bluuebunny/crossref_metadata_2025 huggingface dataset:
A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance
Authors: Huang Lan , Cao Yang , Zhou Jianfang , Qin Kun , Zhu Wenfei , Zhu Yun , Yang Lei , Wang Dayan , Wei Hong , Shu Yuelong
Published: December 2013

The I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site. Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the binding pocket, which otherwise only subtends the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.
A Structural Biology Approach Enables the Development of Antimicrobials Targeting Bacterial Immunophilins
Authors: Begley Darren W. , Fox David , Jenner Dominic , Juli Christina , Pierce Phillip G. , Abendroth Jan , Muruthi Muigai , Safford Kris , Anderson Vanessa , Atkins Kateri , Barnes Steve R. , Moen Spencer O. , Raymond Amy C. , Stacy Robin , Myler Peter J. , Staker Bart L. , Harmer Nicholas J. , Norville Isobel H. , Holzgrabe Ulrike , Sarkar-Tyson Mitali , Edwards Thomas E. , Lorimer Donald D.
Published: December 2013

Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from
Burkholderia pseudomallei
(BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the
in vitro
activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of
Burkholderia pseudomallei
. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.
Genetic Basis for Vancomycin-Enhanced Cephalosporin Susceptibility in Vancomycin-Resistant Enterococci Revealed Using Counterselection with Dominant-Negative Thymidylate Synthase
Authors: Kristich Christopher J. , Djorić Dušanka , Little Jaime L.
Published: December 2013

Antibiotic-resistant enterococci are major causes of hospital-acquired infections. All enterococci are intrinsically resistant to most cephalosporins, antibiotics in the beta-lactam family that impair peptidoglycan synthesis by inactivating the transpeptidases responsible for cross-linking. In addition, clinical isolates of enterococci often possess acquired resistance to vancomycin, a glycopeptide antibiotic that impairs peptidoglycan biosynthesis by a mechanism distinct from that of the beta-lactams, namely, by binding to the
d
-Ala-
d
-Ala termini found in peptidoglycan precursors to prevent their utilization by biosynthetic transglycosylases. Antimicrobial synergism between vancomycin and beta-lactams against vancomycin-resistant enterococci was originally described decades ago, but the genetic basis for synergy has remained unknown. Because a complete understanding of the mechanism underlying synergy between vancomycin and beta-lactams might suggest new targets or strategies for therapeutic intervention against antibiotic-resistant enterococci, we explored the genetic basis for synergy between vancomycin and cephalosporins in
Enterococcus faecalis
. To do so, we developed a counterselection strategy based on a dominant-negative mutant of thymidylate synthase and implemented this approach to create a panel of mutants in vancomycin-resistant
E. faecalis
. Our results confirm that vancomycin promotes synergy by inducing expression of the
van
resistance genes, as a mutant in which the
van
genes are expressed in the absence of vancomycin exhibits susceptibility to cephalosporins. Further, we show that peptidoglycan precursors substituted with
d
-Ala-
d
-Lac are not required for vancomycin-enhanced cephalosporin sensitivity. Instead, production of the
d
,
d
-carboxypeptidase VanY
B
is both necessary and sufficient to dramatically sensitize
E. faecalis
to cephalosporins.
Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction—a phase I pilot clinical trial: study protocol
Authors: Alers Nicole O , Jenkin Graham , Miller Suzanne L , Wallace Euan M
Published: December 2013

Background

Fetal growth restriction complicates about 5% of pregnancies and is commonly caused by placental dysfunction. It is associated with increased risks of perinatal mortality and short-term and long-term morbidity, such as cerebral palsy. Chronic in utero hypoxaemia, inflammation and oxidative stress are likely culprits contributing to the long-term neurological sequelae of fetal growth restriction. In this regard, we propose that melatonin, a powerful antioxidant, might mitigate morbidity and/or mortality associated with fetal growth restriction. Melatonin has an excellent biosafety profile and crosses the placenta and blood–brain barrier. We present the protocol for a phase I clinical trial to investigate the efficacy of maternal oral melatonin administration in women with a pregnancy complicated by fetal growth restriction.

Methods and analysis

The proposed trial is a single-arm, open-label clinical trial involving 12 women. Severe, early onset fetal growth restriction will be diagnosed by an estimated fetal weight ≤10th centile in combination with abnormal fetoplacental Doppler studies, occurring before 34 weeks of pregnancy. Baseline measurements of maternal and fetal well-being, levels of oxidative stress and ultrasound and Doppler measurements will be obtained at the time of diagnosis of fetal growth restriction. Women will then start melatonin treatment (4 mg) twice daily until birth. The primary outcomes are the levels of oxidative stress in the maternal and fetal circulation and placenta. Secondary outcomes are fetoplacental Doppler studies (uterine artery, umbilical artery middle cerebral artery and ductus venosus), fetal biometry, fetal biophysical profile and a composite determination of neonatal outcome. A historical cohort of gestational-matched fetal growth restriction and a healthy pregnancy cohort will be used as comparators.

Ethics and dissemination

Ethical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC12133B). Data will be presented at international conferences and published in peer-reviewed journals.

Trial registration number

Clinical Trials, protocol registration system:NCT01695070.
HIGH-ENERGY DENSITY IMPLICATIONS OF A GRAVITOWEAK UNIFICATION SCENARIO
Authors: ONOFRIO ROBERTO
Published: December 2013

We discuss how a scenario recently proposed for the morphing of macroscopic gravitation into weak interactions at the attometer scale affects our current understanding of high-energy density phenomena. We find that the Yukawa couplings of the fundamental fermions are directly related to their event horizons, setting an upper bound [Formula: see text] for their observability through gauge interactions. Particles with larger Yukawa couplings are not precluded, but should interact only gravitationally, providing a natural candidate for dark matter. Furthermore, the quantum vacuum contribution to the cosmological constant is reduced by several orders of magnitude with respect to the current estimates. The expected running of the Newtonian gravitational constant could provide a viable alternative scenario to the inflationary stage of the Universe.
Tyrosine Phosphatase PTPN22: Multifunctional Regulator of Immune Signaling, Development, and Disease
Authors: Bottini Nunzio , Peterson Erik J.
Published: December 2013

Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell–mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN22-R620W may foster inflammation through modulating the balance of myeloid cell–produced cytokines.
Simulating Growth Kinetics in a Data-Parallel 3D Lattice Photobioreactor
Authors: Husselmann A. V. , Hawick K. A.
Published: December 2013

Though there have been many attempts to address growth kinetics in algal photobioreactors, surprisingly little have attempted an agent-based modelling (ABM) approach. ABM has been heralded as a method of practical scientific inquiry into systems of a complex nature and has been applied liberally in a range of disciplines including ecology, physics, social science, and microbiology with special emphasis on pathogenic bacterial growth. We bring together agent-based simulation with the Photosynthetic Factory (PSF) model, as well as certain key bioreactor characteristics in a visual 3D, parallel computing fashion. Despite being at small scale, the simulation gives excellent visual cues on the dynamics of such a reactor, and we further investigate the model in a variety of ways. Our parallel implementation on graphical processing units of the simulation provides key advantages, which we also briefly discuss. We also provide some performance data, along with particular effort in visualisation, using volumetric and isosurface rendering.
Profiling the Prognosis of Gastric Cancer Patients: Is It Worth Correlating the Survival with the Clinical/Pathological and Molecular Features of Gastric Cancers?
Authors: Lorenzon Laura , Mercantini Paolo , Ferri Mario , La Torre Marco , Sparagna Alessandra , Balducci Genoveffa , Tarantino Giulia , Romiti Adriana , Pilozzi Emanuela , Ziparo Vincenzo
Published: December 2013

Background. The prognosis of gastric cancer patients still remains poor. The aim of this study was investigating the prognostic value of several clinical/pathological/molecular features in a consecutive series of gastric cancers. Methods. 150 R0 gastrectomies plus 77 gastric cancer patients evaluated for the HER2 overexpression were selected. Survival was calculated and patients stratified according to the stage, the T‐stage, the LNRs, the LNH, and the HER2 scoring system. ROC curves were calculated in order to compare the performance of the LRN and LNH systems. Results. Prognosis correlated with the stage and with the T‐stage. We documented a statistical correlation between the LNRs and the survival. Conversely, a LNH > 15 did not correlate with the outcomes. The ROC curves documented a significant performance of the LRN system, whereas a statistical correlation was documented for the LNH exclusively with the endpoint of disease‐free survival. We documented a trend of worse prognosis for patients with an HER2 overexpression, even though it was not of statistical value. Conclusion. The LNR and the evaluation of the HER2 overexpression might be useful since they correlate with survival, might identify patients with a higher risk of recurrence, and might select patients for a tailored medical treatment.
Function ofTiO2Lattice Defects toward Photocatalytic Processes: View of Electronic Driven Force
Authors: Cui Huanan , Liu Hong , Shi Jianying , Wang Chuan
Published: December 2013

Oxygen vacancies and Ti-related defects (OTDs) are the main lattice defects ofTiO2, which have great influence on its photocatalytic activity. To understand the relationship between the defects and photocatalytic activities, detailed discussions based on the electronic driven force provided by these defects are carried out during the three commonly accepted processes in photocatalytic reactions. It is found that these defects inevitably (i) influence the energy structure of the pristineTiO2as the isolate acceptor/donor level or hybrid with the original orbital, (ii) provide a disordered short-range force that confuses the charge carriers transferring to surface active sites, (iii) act not only as the surface active sites for trapping the charge carriers but also as the main chemisorption sites forO2,H2O, and organic species. These effects of the defects make them one of the key factors that determine the efficiency of heterogeneous photocatalysis. Clarifying the role of the defects will further facilitate the exploration and the construction of high-performance photocatalysts for practical applications.
Isolation and Evaluation of Mucilage of Adansonia digitata Linn as a Suspending Agent
Authors: Deshmukh S. S. , Katare Y. S. , Shyale S. S. , Bhujbal S. S. , Kadam S. D. , Landge D. A. , Shah D. V. , Pawar J. B.
Published: December 2013

Natural excipients can serve as alternative to synthetic products because of local accessibility, biodegradability, eco-friendly nature and cost effectiveness as compared to synthetic products. Therefore, it is a current need to explore natural excipients that can be used as an effective alternative excipient for the formulation of pharmaceutical dosage forms. Adansonia digitata (Malvaceae) has been traditionally used as febrifuge, antiasthmatic and also in the treatment of dysentery, smallpox, and measles. Reports have indicated that mucilage of the leaves of the plant is edible and nontoxic; hence, the present study is an attempt of isolation and evaluation of mucilage obtained from leaves of Adansonia digitata as suspending agent. Various physicochemical as well as suspending agent properties of mucilage were studied. Mucilage obtained from leaves has shown comparable results with sodium carboxy methyl cellulose.
Square Wave Voltammetric Determination of 2-Thiouracil in Pharmaceuticals and Real Samples Using Glassy Carbon Electrode
Authors: Gokavi Naveen M. , Pattar Vijay P. , Bagoji Atmanand M. , Nandibewoor Sharanappa T.
Published: December 2013

A simple and rapid method was developed using cyclic and square wave voltammetric techniques for the determination of trace-level sulfur containing compound, 2-thiouracil, at a glassy carbon electrode. 2-thiouracil produced two anodic peaks at 0.334 V and 1.421 V and a cathodic peak at −0.534 V. The square wave voltammetry of 2-thiouracil gave a good linear response in the range of 1–20 μM with a detection limit of 0.16 μM and quantification limit of 0.53 μM (0.0679 μg/g), which is in good agreement as per IUPAC definition of trace component analysis (100 μg/g). The obtained recoveries range from 98.10% to 102.1%. The proposed method was used successfully for its quantitative determination in pharmaceutical formulations and urine as real samples.
Multiple Solutions for Nonhomogeneous Neumann Differential Inclusion Problems by the p(x)‐Laplacian
Authors: Zhou Qing-Mei
Published: December 2013

A class of nonlinear Neumann problems driven by p(x)‐Laplacian with
a nonsmooth locally Lipschitz potential (hemivariational inequality) was considered. The approach used in this paper
is the variational method for locally Lipschitz functions. More precisely, Weierstrass theorem and Mountain Pass
theorem are used to prove the existence of at least two nontrivial solutions.
The Effect of a Maternal Double Megadose of Vitamin A Supplement on Serum Levels of Retinol in Children Aged under Six Months
Authors: Santos Carmina Silva dos , Kruze Ilma , Fernandes Taciana , Andreto Luciana Marques , Figueiroa José Natal , Diniz Alcides da Silva
Published: December 2013

Objective. To measure concentrations of serum retinol in children after the use of maternal vitamin A double megadose supplements.Design. Randomized controlled clinical trial.Setting. The study was conducted at two maternity hospitals in the city of Recife, in the northeast region of Brazil between August 2007 and June 2009.Subjects and Methods. 276 children/mothers were recruited after birth and the women received a 200,000 IU capsule of vitamin A. After ten days they were randomly assigned to two treatment groups. One group received a second 200.000 IU capsule, while the other received a placebo. The concentrations of retinol in the serum of the children from each group were measured at 2, 4, and 6 months.Results. 173 children completed the study. There was no difference between the two treatment groups (P=0.514). The mean base retinol level was lower than that at four and six months (P<0.001).Conclusions. The maternal double megadose supplement had no additional effect on the serum retinol levels of the children, although concentrations of retinol in the children rose in the first six months of life. This trial is registered withNCT00742937.
17β-Estradiol Protects Against the Progression of Hypertension During Adulthood in a Mouse Model of Systemic Lupus Erythematosus
Authors: Gilbert Emily L. , Mathis Keisa W. , Ryan Michael J.
Published: December 2013

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with a high prevalence of hypertension and cardiovascular disease. Because SLE predominantly affects women, estrogen is commonly implicated as a contributor to SLE disease progression. Using an established mouse model of SLE (female NZBWF1), we tested whether estrogen has a causal role in the development of hypertension in adulthood. Thirty-week-old SLE and control mice (NZW/LacJ) underwent either a sham or ovariectomy (OVX) procedure. 17β-Estradiol (E2; 5 μg/mouse, twice/week, subcutaneously) was administered to a subset of OVX mice. Mean arterial pressure (in mm Hg) was increased in SLE mice (134±4 versus 119±3 in controls). Contrary to our hypothesis, OVX exacerbated the hypertension in female SLE mice (153±3;
P
<0.05 versus SLE sham), and repletion of E2 prevented the OVX-induced increase in blood pressure (132±2). The prevalence of albuminuria was increased in SLE mice compared with controls (37% versus 0%). OVX increased the prevalence in SLE mice (70% versus 37% in SLE shams). Repletion of E2 completely prevented albuminuria in OVX SLE mice. Renal cortical tumor necrosis factor α was increased in SLE mice compared with controls and was further increased in OVX SLE. The OVX-induced increase in renal tumor necrosis factor α expression was prevented by repletion of E2. Treatment of OVX SLE mice with the tumor necrosis factor α inhibitor, etanercept, blunted the OVX-induced increase in blood pressure (140±2) and prevalence of albuminuria (22%). These data suggest that 17β-estradiol protects against the progression of hypertension during adulthood in SLE, in part, by reducing tumor necrosis factor α.
‘Christians, out here?’ Encountering Street-Pastors in the post-secular spaces of the UK’s night-time economy
Authors: Middleton Jennie , Yarwood Richard
Published: December 2013

This paper explores the concept of the post-secular city by examining the growing presence of Street-Pastors in the night-time economy of British cities. Street-Pastors are Christian volunteers who work to ensure the safety of people on a ‘night out’. We contribute to work that has called for greater attention to be placed on the ways in which religious faith and ethics are performed to create liminal spaces of understanding in urban areas. Drawing upon in-depth ethnographic research conducted in a range of UK towns and cities, we consider this distinct form of faith-based patrolling in relation to the spatial processes and practices of urban-nightscapes. By exploring the geographies of Street-Pastors, we not only contribute to more nuanced accounts of ‘drinking spaces’ but provide an empirical engagement with the growing body of work on urban rhythms and encounters.
Psychiatric disorder or impairing psychology in children who have been excluded from school: A systematic review
Authors: Whear Rebecca , Marlow Ruth , Boddy Kate , Ukoumunne Obioha C. , Parker Claire , Ford Tamsin , Thompson-Coon Jo , Stein Ken
Published: December 2013

When children with special educational needs are excluded from school, it should raise the concern that these children are not receiving adequate help and support. This systematic review aims to identify the prevalence of psychiatric disorder or impairing psychopathology among children who are excluded from school compared to children who are not excluded from school. The review follows the guidelines set out by the Centre of Research and Dissemination ( Centre for Reviews and Dissemination, 2009 ). We used broad search terms (across 16 databases) in order to avoid missing papers, our initial screening stage involved 3712 titles and abstracts. Five studies finally met our inclusion criteria. The results from these studies suggest that the odds of children who have been excluded from school having some kind of impairing psychological or behavioural impairment is increased in comparison to children who have not been excluded (odds ratios ranging from 1.13–31.9). However, the paucity of primary research in this area, combined with methodological weaknesses in the identified studies makes it difficult to draw firm conclusions. The need for education and mental health professionals to work together to provide the appropriate support for all children at risk of exclusion is of great and immediate concern.
Predictive Factors of Contralateral Paratracheal Lymph Node Metastasis in Papillary Thyroid Cancer: Prospective Multicenter Study
Authors: Eun Young Gyu , Lee Young Chan , Kwon Kee Hwan
Published: December 2013

Objective

To analyze patterns of central lymph node (LN) metastasis to specific compartments in the neck and predictive factors of contralateral paratracheal LN metastasis in patients who underwent prophylactic bilateral central LN dissection for papillary thyroid cancer (PTC).

Study Design

Prospective study.

Setting

Multitertiary centers.

Subjects and Methods

One hundred forty consecutive patients underwent total thyroidectomy and prophylactic bilateral central LN dissection for unilateral PTC without evidence of central LN metastatic disease based on preoperative ultrasound imaging. The central LN compartment was divided into prelaryngeal, ipsilateral/contralateral paratracheal, and pretracheal regions. The patterns of central LN metastasis and clinicopathologic variables for predicting contralateral metastasis were analyzed.

Results

Fifty‐one (36.4%) of 140 patients had nodal involvement in the central compartment. Twelve (23.5%) patients had ipsilateral paratracheal LN metastasis, 17 (33.3%) had ipsilateral paratracheal and pretracheal LN metastasis, 14 (27.5%) had bilateral paratracheal LN metastasis, 9 (17.6%) had pretracheal‐only LN metastasis, and 8 (15.7%) had prelaryngeal LN metastasis. Ipsilateral paratracheal LN metastasis was found to independently predict contralateral paratracheal LN metastasis in patients without central LN metastatic disease.

Conclusions

Contralateral paratracheal LN metastasis is associated with ipsilateral paratracheal LN metastasis. This information may help to determine the optimal extent of prophylactic central LN dissection in patients with PTC.
High-Dose Caspofungin as a Component of Combination Antifungal Therapy in 91 Patients With Neoplastic Diseases and Hematopoietic Stem Cell Transplantation
Authors: Safdar Amar , Rodriguez Gilhen , Zuniga Jorge , Al Akhrass Fadi , Pande Anupam
Published: December 2013

The antifungal activity of echinocandins is concentration dependent. Previously, we demonstrated that high-dose caspofungin (HD-CSP; 100 mg daily) was well tolerated in 34 immunosuppressed patients with cancer and may have favorably influenced outcomes. We retrospectively assessed all 91 patients in whom HD-CSP was given for the treatment of invasive fungal disease (IFD). The median number of doses was 18.5 ± 21.5, and in 8 (9%) patients more than 40 doses were given. Most (62%) of the patients had leukemia. A total of 45 (49%) patients had undergone stem cell transplantation; 80% received allogeneic grafts and 47% had graft-versus-host disease. High-dose corticosteroids were given during antifungal therapy in 26 (29%) patients. In all, 8 (9%) patients had new elevation in serum bilirubin during HD-CSP therapy; normalization occurred after voriconazole and HD-CSP were discontinued in 4 patients each. No other short-term or delayed adverse events were observed. In all, 40 (44%) patients died of IFD. High-dose corticosteroids during HD-CSP (odds ratio [OR] 8, 95% confidence interval [CI] 2.1-30.4; P < .002) and starting HD-CSP in the critical care unit (OR 67.5, 95% CI 5.25-868.9; P < .001) were associated with death from fungal disease. Prolonged HD-CSP therapy was well tolerated. Drug-induced hyperbilirubinemia may pose a potential limitation for continued HD-CSP use in highly susceptible patients with hematologic neoplasms and stem cell transplantation.
Fault tolerant control of large-scale systems subject to actuator fault using a cooperative approach
Authors: Moradi Amani Ali , Poorjandaghi Seyyed Saeed , Afshar Ahmad , Menhaj Mohamad Bagher
Published: December 2013

In this article, a new approach to tackle the problem of fault tolerant control of large-scale systems is proposed. The main goal of this so-called cooperative fault tolerant control approach is to overcome the undesired effects of an actuator fault propagated through the whole large-scale system. This is done using a cooperation of a subset of subsystems. The approach is first clarified through an illustrative example and is then completely formulated. It is then solved in a special case called “cooperative reconfiguration” using the previously defined virtual actuator technique. Finally, results of this article are implemented on the load–frequency control problem of a power system.
A sensorless speed estimation algorithm for use in induction motor fault detection applications
Authors: Bradley William J , Mason Byron , Pezouvanis Antonios , Ebrahimi Kambiz M
Published: December 2013

A novel sensorless speed estimation algorithm for use with direct online three-phase induction motors is proposed. Speed information is extracted from the motor current spectrum by tracking the frequency of key components, which vary as a function of motor rotational speed. An important advantage of this technique is that the speed estimation algorithm is independent of motor mechanical and electrical parameters. The algorithm operates via estimating rotor bar number, which is in turn used to determine rotational speed via rotor bar pass frequency detection including a sanity check on estimated speed via comparison with a linear speed estimate based on rated nameplate data. Experimental results are included for a range of three-phase induction motors including motors carrying faults (bearing, rotor, stator and air-gap eccentricity). The results demonstrate the robustness of the algorithm to motors operating with a variety of faults and thus the potential for use of the algorithm in induction motor fault detection and diagnosis applications.
Trajectory planning and tracking control for multiple-input multiple-output, linear time-invariant, sampled data systems in continuous time
Authors: Lindert Sven-Olaf
Published: December 2013

In applications, usually sampled data controllers are employed. If the sampling time is sufficiently small, the sampled data structure may be neglected and the system is treated quasi-continuously. If the sampling time is longer, the system is treated in discrete time neglecting the behaviour in between the sample instances and the z-transform is used. This article combines these two approaches. The plant is driven by an input which consists of a sequence of values and a function forming the actuating variable. By use of the modified z-transform, the plant is modelled by a parametric transfer function matrix, whose additional parameter discloses the behaviour between sampling instances. Thus, the output signal is calculated not only at the points of sampling. A right co-prime matrix-fraction description is derived. Building on that description, basis variables are defined in the z-domain. The corresponding basis sequences can be chosen arbitrarily and with them the input sequences and the output functions are fixed and can be calculated without solving a differential or difference equation. This mathematical fact is applied to plan trajectories in continuous time. Hence, the entire output trajectory in continuous time can be taken into account. A tracking controller may be added to ensure that the disturbed system complies with the plan.
A Cross-Cultural Examination of Self-Leadership
Authors: Houghton Jeffery D. , Carnes Andrew , Ellison Christopher N.
Published: December 2013

The purpose of this study is to examine the cross-cultural validity of self-leadership by confirming a second-order factor structure and testing for measurement invariance in the operationalization of the self-leadership construct across four distinct national cultures: the United States, China, Germany, and Portugal. Results provide evidence in support of the cross-cultural validity of the hierarchical factor structure of self-leadership and in support of partial metric measurement invariance for the Revised Self-Leadership Questionnaire (RSLQ). Taken together, these findings suggest that future researchers examining substantive self-leadership hypotheses within and across non-U.S. cultures may proceed with confidence.
Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia
Authors: Cortés-Puch Irene , Wang Dong , Sun Junfeng , Solomon Steven B. , Remy Kenneth E. , Fernandez Melinda , Feng Jing , Kanias Tamir , Bellavia Landon , Sinchar Derek , Perlegas Andreas , Solomon Michael A. , Kelley Walter E. , Popovsky Mark A. , Gladwin Mark T. , Kim-Shapiro Daniel B. , Klein Harvey G. , Natanson Charles
Published: December 2013

Key Points

Washing older blood before transfusion reduces plasma iron, improving outcomes from established infection in canines. In contrast, washing fresh blood before transfusion increases in vivo plasma CFH release, worsening outcomes.
Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder
Authors: Balogh Emese , Madruga Dias Joao , Orr Carl , Mullan Ronan , Harty Len , FitzGerald Oliver , Gallagher Phil , Molloy Miriam , O’Flynn Eileen , Kelly Alexia , Minnock Patricia , O’Neill Madeline , Moore Louise , Murray Mairead , Fearon Ursula , Veale Douglas J
Published: December 2013

Introduction

Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.

Methods

Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.

Results

Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).

Conclusions

Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.
Randomized Phase III Study of Erlotinib Versus Observation in Patients With No Evidence of Disease Progression After First-Line Platin-Based Chemotherapy for Ovarian Carcinoma: A European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup Study
Authors: Vergote Ignace B. , Jimeno Antonio , Joly Florence , Katsaros Dionyssios , Coens Corneel , Despierre Evelyn , Marth Christian , Hall Marcia , Steer Christopher B. , Colombo Nicoletta , Lesoin Anne , Casado Antonio , Reinthaller Alexander , Green John , Buck Martin , Ray-Coquard Isabelle , Ferrero Annamaria , Favier Laure , Reed Nick Simon , Curé Hervé , Pujade-Lauraine Eric
Published: December 2013

Purpose

This trial evaluated the efficacy of maintenance erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, after first-line chemotherapy.

Patients and Methods

Eligible patients had high-risk International Federation of Gynecology and Obstetrics stage I or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first-line platinum-based chemotherapy (CT) and showed no signs of progression at the end of CT. Patients were randomly assigned to maintenance erlotinib 150 mg orally daily for 2 years or to observation. EGFR immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutation analyses were performed in 318 patients.

Results

Between October 2005 and February 2008, 835 patients were randomly assigned (median follow-up, 51 months). Twenty-six percent of the patients stopped erlotinib as a result of adverse effects (of these, 67% were due to rash). For erlotinib and observation, respectively, the median progression-free survival was 12.7 and 12.4 months (hazard ratio [HR], 1.05; 95% CI, 0.90 to 1.23), and the median overall survival was 50.8 and 59.1 months (HR, 0.99; 95% CI, 0.81 to 1.20 months), respectively. No subgroup could be identified with improved effect of erlotinib, based on IHC or FISH for EGFR, or mutations in genes related to the EGFR pathway, or on rash during erlotinib therapy. However, patients with a positive FISH EGFR score had a worse overall survival (46.1 months) than those with a negative score (67.0 months; HR, 1.56; 95% CI, 1.01 to 2.40; P = .044). Global health/quality-of-life scores showed a significant difference during the first year (P = .0102) in favor of the observation arm.

Conclusion

Maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival.
Temperate shelf water dispersal by Australian boundary currents: Implications for population connectivity
Authors: Coleman Melinda A. , Feng Ming , Roughan Moninya , Cetina‐Heredia Paulina , Connell Sean D.
Published: December 2013

Lay Abstract

Boundary currents have been recognized as potential causes of spatial variation in the ocean because of their role in physical transport. In this study we used particle tracking methods in an ocean circulation model to determine the effect of multiple boundary currents on connectivity around temperate Australia during the austral winter. Our results demonstrated that oceanographic connectivity was asymmetric around Australia, having greater eastward connectivity due to more favorable ocean boundary currents during this season. We compared connectivity patterns with genetic data from an important marine species, the kelp, Ecklonia radiata, which have more genetic similarity between the west and south coasts of Australia, with the east coast, likely due to predominantly eastward dispersal in currents. Boundary current connectivity was linked to genetic connectivity of kelp on multigeneration time scales and the nature of these relationships varied among the three boundary current systems according to current strength.
Global Analysis of Serine/Threonine and Tyrosine Protein Phosphatase Catalytic Subunit Genes inNeurospora crassaReveals Interplay Between Phosphatases and the p38 Mitogen-Activated Protein Kinase
Authors: Ghosh Arit , Servin Jacqueline A , Park Gyungsoon , Borkovich Katherine A
Published: December 2013

Protein phosphatases are integral components of the cellular signaling machinery in eukaryotes, regulating diverse aspects of growth and development. The genome of the filamentous fungus and model organism Neurospora crassa encodes catalytic subunits for 30 protein phosphatase genes. In this study, we have characterized 24 viable N. crassa phosphatase catalytic subunit knockout mutants for phenotypes during growth, asexual development, and sexual development. We found that 91% of the mutants had defects in at least one of these traits, whereas 29% possessed phenotypes in all three. Chemical sensitivity screens were conducted to reveal additional phenotypes for the mutants. This resulted in the identification of at least one chemical sensitivity phenotype for 17 phosphatase knockout mutants, including novel chemical sensitivities for two phosphatase mutants lacking a growth or developmental phenotype. Hence, chemical sensitivity or growth/developmental phenotype was observed for all 24 viable mutants. We investigated p38 mitogen-activated protein kinase (MAPK) phosphorylation profiles in the phosphatase mutants and identified nine potential candidates for regulators of the p38 MAPK. We demonstrated that the PP2C class phosphatase pph-8 (NCU04600) is an important regulator of female sexual development in N. crassa. In addition, we showed that the Δcsp-6 (ΔNCU08380) mutant exhibits a phenotype similar to the previously identified conidial separation mutants, Δcsp-1 and Δcsp-2, that lack transcription factors important for regulation of conidiation and the circadian clock.
A Genetic Screen for Functional Partners of Condensin in Fission Yeast
Authors: Robellet Xavier , Fauque Lydia , Legros Pénélope , Mollereau Esther , Janczarski Stéphane , Parrinello Hugues , Desvignes Jean-Pierre , Thevenin Morgane , Bernard Pascal
Published: December 2013

Mitotic chromosome condensation is a prerequisite for the accurate segregation of chromosomes during cell division, and the conserved condensin complex a central player of this process. However, how condensin binds chromatin and shapes mitotic chromosomes remain poorly understood. Recent genome-wide binding studies showing that in most species condensin is enriched near highly expressed genes suggest a conserved link between condensin occupancy and high transcription rates. To gain insight into the mechanisms of condensin binding and mitotic chromosome condensation, we searched for factors that collaborate with condensin through a synthetic lethal genetic screen in the fission yeast Schizosaccharomyces pombe. We isolated novel mutations affecting condensin, as well as mutations in four genes not previously implicated in mitotic chromosome condensation in fission yeast. These mutations cause chromosome segregation defects similar to those provoked by defects in condensation. We also identified a suppressor of the cut3-477 condensin mutation, which largely rescued chromosome segregation during anaphase. Remarkably, of the five genes identified in this study, four encode transcription co-factors. Our results therefore provide strong additional evidence for a functional connection between chromosome condensation and transcription.
Is Treatment Futile for an Extremely Premature Infant With Giant Omphalocele?
Authors: Feltman Dalia , Stokes Theophil , Kett Jennifer , Lantos John D.
Published: December 2013

Doctors have no ethical obligation to provide futile treatment. This has been true since the time of Hippocrates who warned physicians not to treat patients who were “overmastered by their disease.” This principle remains valid today but, as the Society for Critical Care Medicine notes, it is difficult to identify treatment as absolutely futile in all but a few clinical situations. Far more common, they note, are “treatments that are extremely unlikely to be beneficial, are extremely costly, or are of uncertain benefit.” These, they say, “may be considered inappropriate and hence inadvisable, but should not be labeled futile.” So what should doctors do when they have a case that seems close to the futility threshold but does not, perhaps, quite cross it? In such cases, is it appropriate to make unilateral decisions to withhold life-sustaining treatment even if the family objects? Or should treatment be provided knowing that it might cause pain and suffering to an infant with no likelihood of benefit? To address these questions, we present a case of an extremely premature infant with a giant omphalocele and ask 3 neonatologists, Dr Dalia Feltman of Evanston Hospital, Dr Theophil Stokes of the Walter Reed Medical Center, and Dr Jennifer Kett, a neonatologist and fellow in bioethics at Seattle Children’s Hospital, to comment.
Association Study between IL-1β−511 C/T Polymorphism and Obsessive-Compulsive Disorder (OCD) in Chinese Han Population
Authors: Bo Yongli , Liu Shiguo , Yin Yingying , Wang Zusen , Cui Jiajia , Zong Jinbao , Zhang Xinhua , Li Xingang
Published: December 2013

Aim:

This study investigated the potential association between Obsessive-Compulsive Disorder (OCD) and a functional polymorphism of IL-1β−511 C/T in Chinese Han population.

Methods:

The authors genotyped the IL-1β−511 C/T of 241 OCD patients and 444 healthy control subjects and then performed a case-control association analysis.

Results:

No difference was found in IL-1β−511 C/T genotypic and allelic frequencies between OCD cases and controls (χ2 = 0.501, df = 2, P = 0.78 by genotype; χ2 = 0.487, df = 1, P = 0.49 by allele).

Conclusion:

IL-1β−511 polymorphism may not play a major role in the genetic predisposition to OCD in Chinese Han population. Given that this is an early investigation of this gene in OCD, further studies are required to draw firm conclusions.
High-Level Expression of Pro-Form Lipase from Rhizopus oryzae in Pichia pastoris and Its Purification and Characterization
Authors: Wang Jian-Rong , Li Yang-Yuan , Xu Shu-De , Li Peng , Liu Jing-Shan , Liu Dan-Ni
Published: December 2013

A gene encoding Rhizopus oryzae lipase containing prosequence (ProROL) was cloned into the pPICZαA and electrotransformed into the Pichia pastoris X-33 strain. The lipase was functionally expressed and secreted in Pichia pastoris with a molecular weight of 35 kDa. The maximum lipase activity of recombinant lipase (rProROL) was 21,000 U/mL, which was obtained in a fed-batch cultivation after 168 h induction with methanol in a 50-L bioreactor. After fermentation, the supernatant was concentrated by ultrafiltration with a 10 kDa cut off membrane and purified with ion exchange chromatography using SP Sepharose Fast Flow chromatography. The optimum pH and temperature of the rProROL were pH 9.0 and 40 °C, respectively. The lipase was stable from pH 4.0 to 9.0 and from 25 to 55 °C. The enzyme activity was enhanced by Ca2+ and inhibited by Hg2+ and Ag+. The lipase showed high activity toward triglyceride-Tripalmitin (C16:0) and triglyceride-Trilaurin (C12:0).
6-Bromoisatin Found in Muricid Mollusc Extracts Inhibits Colon Cancer Cell Proliferation and Induces Apoptosis, Preventing Early Stage Tumor Formation in a Colorectal Cancer Rodent Model
Authors: Esmaeelian Babak , Abbott Catherine , Le Leu Richard , Benkendorff Kirsten
Published: December 2013

Muricid molluscs are a natural source of brominated isatin with anticancer activity. The aim of this study was to examine the safety and efficacy of synthetic 6-bromoisatin for reducing the risk of early stage colorectal tumor formation. The purity of 6-bromoisatin was confirmed by 1H NMR spectroscopy, then tested for in vitro and in vivo anticancer activity. A mouse model for colorectal cancer was utilized whereby colonic apoptosis and cell proliferation was measured 6 h after azoxymethane treatment by hematoxylin and immunohistochemical staining. Liver enzymes and other biochemistry parameters were measured in plasma and haematological assessment of the blood was conducted to assess potential toxic side-effects. 6-Bromoisatin inhibited proliferation of HT29 cells at IC50 223 μM (0.05 mg/mL) and induced apoptosis without increasing caspase 3/7 activity. In vivo 6-bromoisatin (0.05 mg/g) was found to significantly enhance the apoptotic index (p ≤ 0.001) and reduced cell proliferation (p ≤ 0.01) in the distal colon. There were no significant effects on mouse body weight, liver enzymes, biochemical factors or blood cells. However, 6-bromoisatin caused a decrease in the plasma level of potassium, suggesting a diuretic effect. In conclusion this study supports 6-bromoisatin in Muricidae extracts as a promising lead for prevention of colorectal cancer.
Stem-Cell-Based Gene Therapy for HIV Infection
Authors: Zhen Anjie , Kitchen Scott
Published: December 2013

Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells.