bluuebunny/crossref_metadata_2025 huggingface dataset:
The bacterial alarmone (p)ppGpp is required for virulence and controls cell size and survival of Pseudomonas syringae on plants
Authors: Chatnaparat Tiyakhon , Li Zhong , Korban Schuyler S. , Zhao Youfu
Published: January 2015

The stringent response, mediated by second messenger (p)ppGpp, results in swift and massive transcriptional reprogramming under nutrient limited conditions. In this study, the role of (p)ppGpp on virulence of Pseudomonas syringae pv. syringae B728a (PssB728a) was investigated. The virulence of the relA/spoT (ppGpp0) double mutant was completely impaired on bean, and bacterial growth was significantly reduced, suggesting that (p)ppGpp is required for full virulence of P. syringae. Expression of T3SS and other virulence genes was reduced in ppGpp0 mutants. In addition, ppGpp deficiency resulted in loss of swarming motility, reduction of pyoverdine production, increased sensitivity to oxidative stress and antibiotic tolerance, as well as reduced ability to utilize γ‐amino butyric acid. Increased levels of ppGpp resulted in reduced cell size of PssB728a when grown in a minimal medium and on plant surfaces, while most ppGpp0 mutant cells were not viable on plant surfaces 24 h after spray inoculation, suggesting that ppGpp‐mediated stringent response temporarily limits cell growth, and might control cell survival on plants by limiting their growth. These results demonstrated that ppGpp‐mediated stringent response plays a central role in P. syringae virulence and survival and indicated that ppGpp serves as a global signal for regulating various virulence traits in PssB728a.
The MADS‐box transcription factor FgMcm1 regulates cell identity and fungal development in Fusarium graminearum
Authors: Yang Cui , Liu Huiquan , Li Guotian , Liu Meigang , Yun Yingzi , Wang Chenfang , Ma Zhonghua , Xu Jin‐Rong
Published: January 2015

In eukaryotic cells, MADS‐box genes are known to play major regulatory roles in various biological processes by combinatorial interactions with other transcription factors. In this study, we functionally characterized the FgMCM1 MADS‐box gene in Fusarium graminearum, the causal agent of wheat and barley head blight. Deletion of FgMCM1 resulted in the loss of perithecium production and phialide formation. The Fgmcm1 mutant was significantly reduced in virulence, deoxynivalenol biosynthesis and conidiation. In yeast two‐hybrid assays, FgMcm1 interacted with Mat1‐1‐1 and Fst12, two transcription factors important for sexual reproduction. Whereas Fgmcm1 mutants were unstable and produced stunted subcultures, Fgmcm1 mat1‐1‐1 but not Fgmcm1 fst12 double mutants were stable. Furthermore, spontaneous suppressor mutations occurred frequently in stunted subcultures to recover growth rate. Ribonucleic acid sequencing analysis indicated that a number of sexual reproduction‐related genes were upregulated in stunted subcultures compared with the Fgmcm1 mutant, which was downregulated in the expression of genes involved in pathogenesis, secondary metabolism and conidiation. We also showed that culture instability was not observed in the Fvmcm1 mutants of the heterothallic Fusarium verticillioides. Overall, our data indicate that FgMcm1 plays a critical role in the regulation of cell identity, sexual and asexual reproduction, secondary metabolism and pathogenesis in F. graminearum.
The loss of function of PhaC1 is a survival mechanism that counteracts the stress caused by the overproduction of poly‐3‐hydroxyalkanoates in Pseudomonas putidaΔfadBA
Authors: Obeso José I. , Maestro Beatriz , Sanz Jesús M. , Olivera Elías R. , Luengo José M.
Published: January 2015

The poly‐3‐hydroxylkanoate (PHA)‐overproducing mutant Pseudomonas putida U ΔfadBA (PpΔfadBA) lacks the genes encoding the main β‐oxidation pathway (FadBA). This strain accumulates enormous amounts of bioplastics when cultured in chemically defined media containing PHA precursors (different n‐alkanoic or n‐aryl‐alkanoic acids) and an additional carbon source. In medium containing glucose or 4‐hydroxy‐phenylacetate, the mutant does not accumulate PHAs and grows just as the wild type (P. putida U). However, when the carbon source is octanoate, growth is severely impaired, suggesting that in PpΔfadBA, the metabolic imbalance resulting from a lower rate of β‐oxidation, together with the accumulation of bioplastics, causes severe physiological stress. Here, we show that PpΔfadBA efficiently counteracts this latter effect via a survival mechanism involving the introduction of spontaneous mutations that block PHA accumulation. Surprisingly, genetic analyses of the whole pha cluster revealed that these mutations occurred only in the gene encoding one of the polymerases (phaC1) and that the loss of PhaC1 function was enough to prevent PHA synthesis. The influence of these mutations on the structure of PhaC1 and the existence of a protein–protein (PhaC1–PhaC2) interaction that explains the functionality of the polymerization system are discussed herein.
Community composition and population genetics of insect pathogenic fungi in the genus Metarhizium from soils of a long‐term agricultural research system
Authors: Kepler Ryan M. , Ugine Todd A. , Maul Jude E. , Cavigelli Michel A. , Rehner Stephen A.
Published: January 2015

Fungi in the genus Metarhizium are insect pathogens able to function in other niches, including soil and plant rhizosphere habitats. In agroecosystems, cropping and tillage practices influence soil fungal communities with unknown effects on the distribution of Metarhizium, whose presence can reduce populations of crop pests. We report results from a selective media survey of Metarhizium in soils sampled from a long‐term experimental farming project in the mid‐Atlantic region. Field plots under soybean cultivation produced higher numbers of Metarhizium colony‐forming units (cfu) than corn or alfalfa. Plots managed organically and via chisel‐till harboured higher numbers of Metarhizium cfu than no‐till plots. Sequence typing of Metarhizium isolates revealed four species, with M. robertsii and M. brunneum predominating. The M. brunneum population was essentially fixed for a single clone as determined by multilocus microsatellite genotyping. In contrast, M. robertsii was found to contain significant diversity, with the majority of isolates distributed between two principal clades. Evidence for recombination was observed only in the most abundant clade. These findings illuminate multiple levels of Metarhizium diversity that can be used to inform strategies by which soil Metarhizium populations may be manipulated to exert downward pressure on pest insects and promote plant health.
Craft and Capacity in the Public Service
Authors: Tiernan Anne
Published: January 2015

Over the past 8 years, debates about Australia's public service have evolved from being focused mainly on skills and capacities to being now increasingly concerned about the operating environment for career officials, their ability to fulfil their stewardship obligations, and to practice their ‘craft’. In this article, I track those changes and ask what is the craft of public administration? How should we understand it? Are concerns it is imperilled or has been lost valid or overblown? I draw on the observations of current and former senior officials, and the findings of recent Capability Reviews. My primary focus is on the Australian Public Service, because here is where the debate has been most public and direct. I note that the focus of concern has shifted from public servants towards ministers, who have been largely absent from public sector reform initiatives of the past 40 years.
Learning about common and private values in oligopoly
Authors: Bernhardt Dan , Taub Bart
Published: January 2015

We characterize a duopoly buffeted by demand and cost shocks. Firms learn about shocks from common observation, private observation, and noisy price signals. Firms internalize how outputs affect a rival's signal, and hence output. We distinguish how the nature of information —public versus private—and of what firms learn about—common versus private values—affect equilibrium outcomes. Firm outputs weigh private information about private values by more than common values. Thus, prices contain more information about private‐value shocks.
Into the Words: Using Statutory Text to Explore the Impact of Federal Courts on State Policy Diffusion
Authors: Hinkle Rachael K.
Published: January 2015

I examine the impact federal appellate courts have on state policy diffusion through the use of computational text analysis. Using a dyadic framework, I model the impact courts have on the decision to adopt a policy and, if adopted, how much text to borrow directly from another state's preexisting law. A court decision ruling a statute unconstitutional can generate up to a 28% relative reduction in the probability of adoption, and a ruling of constitutionality can both increase the probability of adoption by a similar amount and more than double the amount of borrowed text. These findings shed light on how states learn from one another.
Life satisfaction, general well‐being and costs of treatment for severe fear of childbirth in nulliparous women by psychoeducative group or conventional care attendance
Authors: Rouhe Hanna , Salmela‐Aro Katariina , Toivanen Riikka , Tokola Maiju , Halmesmäki Erja , Saisto Terhi
Published: January 2015

Objective

Fear of childbirth is a common reason for seeking cesarean section. It is important to consider outcomes and costs associated with alternative treatment and delivery mode. We compared well‐being and costs of group psychoeducation and conventional care for fear of childbirth.

Design

Randomized controlled trial.

Population

A total of 371 nulliparous women scoring over the 95th centile in the Wijma Delivery Expectancy Questionnaire (W‐DEQ) during the first trimester.

Setting

Finland, data from obstetrical patient records and questionnaires.

Methods

Randomization to group psychoeducation with relaxation (six sessions during pregnancy, one after childbirth, n = 131), or surveillance and referral on demand (n = 240).

Main outcome measures

All costs in maternity care during pregnancy, delivery and postnatally according to Diagnoses Related Groups. Life satisfaction and general well‐being 3 months after childbirth (by a Satisfaction with Life Scale and Well‐being Visual Analogue Scale).

Results

The groups did not differ in total direct costs (€3786/woman in psychoeducative group and €3830/woman in control group), nor in life satisfaction or general well‐being. Although only 76 (30%) of the women assigned to the surveillance were referred to special maternity care and 36 (15%) attended advanced prenatal classes, costs in the psychoeducation group did not exceed the costs of the controls, mostly because of the greater number of uncomplicated vaginal deliveries (63% vs. 47%, p = 0.005).

Conclusions

Through an association with safer childbirth and equal well‐being after delivery, psychoeducative group treatment for nulliparous women with fear of childbirth can be a recommended choice for the same overall costs as conventional treatment.
Biologic Response of Inguinal Hernia Prosthetics: A Comparative Study of Conventional Static Meshes Versus 3D Dynamic Implants
Authors: Amato Giuseppe , Romano Giorgio , Agrusa Antonino , Marasa Salvatore , Cocorullo Gianfranco , Gulotta Gaspare , Goetze Thorsten , Puleio Roberto
Published: January 2015

Despite improvements in prosthetics and surgical techniques, the rate of complications following inguinal hernia repair remains high. Among these, discomfort and chronic pain have become a source of increasing concern among surgeons. Poor quality of tissue ingrowth, such as thin scar plates or shrinking scars—typical results with conventional static implants and plugs—may contribute to these adverse events. Recently, a new type of 3D dynamically responsive implant was introduced to the market. This device, designed to be placed fixation‐free, seems to induce ingrowth of viable and structured tissue instead of regressive fibrotic scarring. To elucidate the differences in biologic response between the conventional static meshes and this 3D dynamically responsive implant, a histological comparison was planned. The aim of this study was to determine the quality of tissue incorporation in both types of implants excised after short, medium, and long periods post‐implantation. The results showed large differences in the biologic responses between the two implant types. Histologically, the 3D dynamic implant showed development of tissue elements more similar to natural abdominal wall structures, such as the ingrowth of loose and well‐hydrated connective tissue, well‐formed vascular structures, elastic fibers, and mature nerves, with negligible or absent inflammatory response. All these characteristics were completely absent in the conventional static implants, where a persistent inflammatory reaction was associated with thin, hardened, and shrunken fibrotic scar formation. Consequently, as herniation is a degenerative process, the 3D dynamic implants, which induce regeneration of the typical groin components, seem to address its pathogenesis.
Use of Blood Products in Pediatric Cardiac Surgery
Authors: Durandy Yves
Published: January 2015

In pediatric cardiac surgery, there is a substantial gap between published recommendations or guidelines for blood product use and clinical practice. The drawbacks of blood transfusion are well acknowledged though. The aim of this paper is to present the rationale for packed red blood cells, fresh frozen plasma (FFP), and platelets used in pediatric patients. Blood hemoglobin level is the current trigger used for packed red blood cells transfusion, though commonly admitted to be suboptimal. An increase in hemoglobin level is likely to be associated with an increase in blood oxygen content and blood oxygen delivery. However, above a critical level of hemoglobin, normovolemic anemia is well tolerated, and any increase in hemoglobin will fail to increase oxygen consumption and therefore to improve end‐organ oxygen supply. FFP is one way to address the coagulation factors deficiency induced by hemodilution, consumption, or hepatic insufficiency. The volume needed to increase these factors is not negligible. To avoid dilution and/or fluid overload, the use of clotting factor concentrate is recommended. The same remark can be made regarding the treatment of antithrombin III deficiency. Platelets infusion should be restricted to bleeding patients with thrombocytopenia and without surgical bleeding. In clinical studies, the prevention of bleeding through prophylactic infusion of platelets proved to be useless. Optimizing the use of blood products (avoiding overuse, underuse, and inappropriate use) is a challenging task in pediatric cardiac surgery. Data or guidelines cannot replace clinical judgment and the decision to transfuse is left to individual discretion, but the medical community needs to optimize its transfusion practice, otherwise policy‐makers without similar expertise may step in to regulate the use of blood products.
Elevated transaminases are common in children on prophylactic treatment for tuberculosis
Authors: Leeb Sara , Buxbaum Charlotte , Fischler Björn
Published: January 2015

Aim

The aim of this study was to assess the prevalence of elevated transaminase levels in children undergoing prophylactic treatment for tuberculosis (TB) infection.

Methods

All children living in a geographically defined area, who started TB prophylaxis during 2009–2011, were included. Data on background factors, treatment regimes and transaminase levels at baseline and follow‐up were collected retrospectively.

Results

Of the 277 children who were treated, 113 (41%) had elevated transaminase levels. Of these, 97 (35%) had levels that were less than three times the upper limit of the normal range and 16 (6%) had levels that were more than three times the normal range. Four patients had to discontinue isoniazid treatment and were successfully switched to rifampicin. In 17 patients, the highest transaminase peak did not occur until after 6 months of treatment. Elevated transaminases were significantly more common in patients below 9 years of age (62%) than in those aged 10–18 years (28%). Transaminases were elevated in 44% of all boys and 36% of all girls (p = 0.17).

Conclusion

Transaminase elevation was common in children receiving prophylactic treatment for TB and started at different points throughout the treatment period. Younger patients faced an increased risk. Regular blood tests are recommended throughout treatment.
Atypical sensory processing is common in extremely low gestational age children
Authors: Rahkonen Petri , Lano Aulikki , Pesonen Anu‐Katriina , Heinonen Kati , Räikkönen Katri , Vanhatalo Sampsa , Autti Taina , Valanne Leena , Andersson Sture , Metsäranta Marjo
Published: January 2015

Aim

Atypical sensory processing is common in children born extremely prematurely. We investigated sensory processing abilities in extremely low gestational age (ELGA) children and analysed associated neonatal risk factors, neuroanatomical findings and neurodevelopmental outcome.

Methods

We carried out a prospective study of 44 ELGA children, including 42 who had undergone brain magnetic resonance imaging (MRI) at term‐equivalent age, when they were 2 years of corrected age. Their sensory processing abilities were assessed with the Infant/Toddler Sensory Profile questionnaire and their neurodevelopmental with a structured Hempel neurological examination, Griffiths Mental Developmental Scales and Bayley Scales of Infant and Toddler Development Third Edition.

Results

Sensory profiles were definitely or probably atypical (<−1 SD) in half of the ELGA children, and the most common behavioural pattern was low registration (23%). Sensation seeking was associated with abnormalities in grey and/or white matter in the brain MRI (p < 0.01). Atypical oral sensory processing was associated with surgical closure of the patent ductus arteriosus (p = 0.02, adjusted p < 0.01).

Conclusion

Atypical sensory processing in ELGA children was common, and children with neonatal neuroanatomical lesions tended to present specific behavioural responses to sensory stimuli. Surgical closure of the patent ductus arteriosus may predispose infants to feeding problems due to atypical oral sensory processing.
The diagnostic criteria for allergic bronchopulmonary aspergillosis in children with poorly controlled asthma need to be re‐evaluated
Authors: Singh Meenu , Das Subhamoy , Chauhan Anil , Paul Nandini , Sodhi Kushaljit Singh , Mathew Joseph , Chakrabarti Arunaloke
Published: January 2015

Aim

The aim of this study was to examine the association between allergic bronchopulmonary aspergillosis (ABPA) and poorly controlled asthma in children and appraise the diagnostic criteria.

Methods

The study included 100 children with poorly controlled asthma. We diagnosed ABPA using the Aspergillus skin test, pulmonary function test, total and specific immunoglobulin E (IgE) to Aspergillus fumigatus, chest radiograph and high‐resolution computed tomography. Patients were diagnosed and classified according to the Rosenberg–Patterson criteria for ABPA. The cut‐off value for total serum IgE was calculated by receiver operating characteristics curve analysis.

Results

Of 100 children with poorly controlled asthma, 26 patients were ABPA positive. There was a significant difference in the forced expiratory volume in 1‐sec/forced vital capacity ratio between ABPA positive (0.78 ± 0.14) and negative (0.87 ± 0.15) children (p = 0.008). ABPA positive children were categorised as seropositive, central bronchiectasis and other radiological findings. The receiver operating characteristics curve was constructed, and a value of 1200 IU/mL of total IgE was observed, with 88.5% sensitivity and 70.5% specificity.

Conclusion

This study showed an association between ABPA and poorly controlled asthma in children and suggests a higher cut‐off value of total IgE for the diagnosis of ABPA.
Toxoplasma prevalence among pregnant women in Norway: a cross‐sectional study
Authors: Findal Gry , Barlinn Regine , Sandven Irene , Stray‐Pedersen Babill , Nordbø Svein A. , Samdal Helvi H. , Vainio Kirsti , Dudman Susanne G. , Jenum Pål A.
Published: January 2015

Infection by Toxoplasma gondii may lead to complications in the foetus if the mother suffers from primary infection during pregnancy. Previously infected women have produced toxoplasma‐specific IgG antibodies. The most recent study on prevalence of toxoplasma IgG in the Norwegian pregnant population was conducted 20 years ago. The present study is part of a research programme initiated by the Norwegian Institute of Public Health. We aimed to update the knowledge regarding the prevalence of toxoplasma IgG among pregnant women in Norway. In this cross‐sectional study, sera from 1922 pregnant women in Buskerud (992) and Sør‐Trøndelag counties (930) in Norway were collected consecutively. The presence of toxoplasma IgG was identified by values ≥8 IU/mL using an ELISA test. The overall prevalence of toxoplasma IgG seropositivity was 9.3% (95% CI 8.1–10.7); Sør‐Trøndelag 10.4% (95% CI 8.6–12.6) and Buskerud 8.3% (95% CI 6.7–10.2). There was no difference between the counties (p = 0.13), and the result did not differ from prevalences found in 1974 (12.1%) and 1994 (10.7%). We found a higher prevalence among women ≥40 years (OR 2.65, 95% CI 1.30–5.42). The prevalence of toxoplasma IgG among pregnant women in Norway is low and has been stable during the last decades.
First report of the blaVIM gene in environmental isolates of Buttiauxella sp.
Authors: Pitondo‐Silva André , Martins Vinicius Vicente , Stehling Eliana Guedes
Published: January 2015

Several works have demonstrated the presence of metallo‐β‐lactamases (MBLs) in clinical bacteria. However, in environmental isolates, few works have reported on these enzymes. In this study, we report for the first time two environmental isolates of Buttiauxella sp. recovered from chrysanthemum plantations in Brazil containing blaVIM gene and producing MBLs.
Virological outcomes and treatment algorithms utilisation in observational study of patients with chronic hepatitis C treated with boceprevir or telaprevir
Authors: Sterling R. K. , Kuo A. , Rustgi V. K. , Sulkowski M. S. , Stewart T. G. , Fenkel J. M. , El‐Genaidi H. , Mah'moud M. A. , Abraham G. M. , Stewart P. W. , Akushevich L. , Nelson D. R. , Fried M. W. , Di Bisceglie A. M.
Published: January 2015

Background

HCV‐TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct‐acting anti‐viral agents (DAAs) in a US consortium of 90 academic and community medical centres.

Aim

To assess utilisation of response‐guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients.

Methods

Patients received peginterferon (PEG‐IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow‐up. RGT and treatment futility stopping rules was assessed at key time points.

Results

Of 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24–40) and 50% (95% CI: 44–56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42–50) and 60% (95% CI: 57–64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients.

Conclusions

In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811.
Generalized Multilevel Function-on-Scalar Regression and Principal Component Analysis
Authors: Goldsmith Jeff , Zipunnikov Vadim , Schrack Jennifer
Published: January 2015

This manuscript considers regression models for generalized, multilevel functional responses: functions are generalized in that they follow an exponential family distribution and multilevel in that they are clustered within groups or subjects. This data structure is increasingly common across scientific domains and is exemplified by our motivating example, in which binary curves indicating physical activity or inactivity are observed for nearly 600 subjects over 5 days. We use a generalized linear model to incorporate scalar covariates into the mean structure, and decompose subject-specific and subject-day-specific deviations using multilevel functional principal components analysis. Thus, functional fixed effects are estimated while accounting for within-function and within-subject correlations, and major directions of variability within and between subjects are identified. Fixed effect coefficient functions and principal component basis functions are estimated using penalized splines; model parameters are estimated in a Bayesian framework using Stan, a programming language that implements a Hamiltonian Monte Carlo sampler. Simulations designed to mimic the application have good estimation and inferential properties with reasonable computation times for moderate datasets, in both cross-sectional and multilevel scenarios; code is publicly available. In the application we identify effects of age and BMI on the time-specific change in probability of being active over a 24-hour period; in addition, the principal components analysis identifies the patterns of activity that distinguish subjects and days within subjects.
Sensory evoked potentials of the bladder and urethra in middle‐aged women: the effect of age
Authors: Gregorini Flavia , Knüpfer Stephanie C. , Liechti Martina D. , Schubert Martin , Curt Armin , Kessler Thomas M. , Mehnert Ulrich
Published: January 2015

Objectives

To investigate feasibility, reproducibility and age dependency of sensory evoked cortical potentials (SEPs) after electrical stimulation of different locations in the lower urinary tract (LUT) in a cohort of middle‐aged healthy women.

Subjects and Methods

In a group of 10 healthy middle‐aged women [mean (sd) height 165 (5) cm and age 43 (6) years), electrical stimulation (0.5 and 3 Hz) was applied to the bladder dome, trigone, and proximal and distal urethra. SEPs were recorded at the Cz electrode with reference to Fz. All measurements were repeated three times with an interval of 3–5 weeks. Current perception thresholds (CPT), SEP latencies and amplitudes were analysed. Results were compared with a group of younger women published previously.

Results

LUT SEPs demonstrated two positive (P1, P2) and one negative peak (N1). The mean (sd) N1 latency was 108.9 (7.8), 116.2 (10.7), 113.2 (13.4) and 131.3 (35.6) ms for the bladder dome, trigone, proximal and distal urethra, respectively. N1 latencies, except for the distal urethra, were significantly shorter than those in younger women. Taking all data, i.e. young and middle‐aged women, into account, there was a significant negative correlation between the variable age and CPT/dome (r = −0.462, P = 0.04) and N1 latency/dome (r = −0.605, P = 0.005) and a significant positive correlation between the variable age and N1P2 amplitude/dome (r = 0.542, P = 0.014).

Conclusion

LUT SEPs can be induced in middle‐aged women with reliable N1 responses. Unexpectedly, N1 responses reveal a shortening with increasing age particularly when compared with younger women. Changes in sensory afferents may be explained by age‐related qualitative reorganisations within the urothelium and suburothelium potentially altering afferent nerve excitability, which may have an impact on the development of non‐neurological LUT symptoms (LUTS, e.g. overactive bladder) in women.
NKCC2 activity is inhibited by the Bartter's syndrome type 5 gain‐of‐function CaR‐A843E mutant in renal cells
Authors: Carmosino Monica , Gerbino Andrea , Hendy Geoffrey N. , Torretta Silvia , Rizzo Federica , Debellis Lucantonio , Procino Giuseppe , Svelto Maria
Published: January 2015

Background information

The gain‐of‐function A843E mutation of the calcium sensing receptor (CaR) causes Bartter syndrome type 5. Patients carrying this CaR variant show a remarkably reduced renal NaCl reabsorption in the thick ascending limb (TAL) of Henle's loop resulting in renal loss of NaCl in the absence of mutations in renal Na+ and Cl− ion transporters. The molecular mechanisms underlying this clinical phenotype are incompletely understood. We investigated, in human embryonic kidney 293 (HEK 293) cells and porcine kidney epithelial (LLC‐PK1) cells, the functional cross‐talk of CaR‐A843E with the Na+:K+:2Cl– co‐transporter, NKCC2, which provides NaCl reabsorption in the TAL.

Results

The expression of the CaR mutant did not alter the apical localisation of NKCC2 in LLC‐PK1 cells. However, the steady‐state NKCC2 phosphorylation and activity were decreased in cells transfected with CaR‐A843E compared with the control wild‐type CaR (CaR WT)‐transfected cells. Of note, low‐Cl−‐dependent NKCC2 activation was also strongly inhibited upon the expression of CaR‐A843E mutant. The use of either P450 ω‐hydroxylase (CYP4)‐ or phospholipase A2 (PLA2)‐blockers suggests that this effect is likely mediated by arachidonic acid (AA) metabolites.

Conclusions

The data suggested that the activated CaR affects intracellular pathways modulating NKCC2 activity rather than NKCC2 intracellular trafficking in renal cells, and throw further light on the pathological role played by active CaR mutants in Bartter syndrome type 5.
Detecting and targetting oncogenic fusion proteins in the genomic era
Authors: Davare Monika A. , Tognon Cristina E.
Published: January 2015

The advent of widespread cancer genome sequencing has accelerated our understanding of the molecular aberrations underlying malignant disease at an unprecedented rate. Coupling the large number of bioinformatic methods developed to locate genomic breakpoints with increased sequence read length and a deeper understanding of coding region function has enabled rapid identification of novel actionable oncogenic fusion genes. Using examples of kinase fusions found in liquid and solid tumours, this review highlights major concepts that have arisen in our understanding of cancer pathogenesis through the study of fusion proteins. We provide an overview of recently developed methods to identify potential fusion proteins from next‐generation sequencing data, describe the validation of their oncogenic potential and discuss the role of targetted therapies in treating cancers driven by fusion oncoproteins.
Design, Synthesis, and In Vitro Evaluation of Novel 3, 7‐Disubstituted Coumarin Derivatives as Potent Anticancer Agents
Authors: Wang Yubin , Liu Haitao , Lu Peng , Mao Rui , Xue Xiaojian , Fan Chen , She Jinxiong
Published: January 2015

Twenty‐seven 3, 7‐disubstituted coumarin derivatives were designed, synthesized, and evaluated in vitro as anticancer agents. Most of the compounds showed moderate‐to‐potent antiproliferative activity against K562 cells. Compounds 7b and 7d were chosen to evaluate the concentration of 50% growth inhibition (GI50) against SN12C, OVCAR, BxPC‐3, KATO‐III, T24, SNU‐1, WiDr, HeLa, K562, and AGS cell lines. The most potent compound 7d was selected for further cell cycle arrest assay in the AGS cell line. The in vitro data indicated that methylation of benzimidazole moiety at the 3‐position of coumarin exhibited significant enhancement of anticancer activity. This study should provide important information for further modification and optimization of coumarin derivatives as anticancer agents.
Implications of less‐than‐perfect reliability of clinical parameters for the misclassification of periodontitis
Authors: Corraini Priscila , Lopez Rodrigo , Vaeth Michael
Published: January 2015

Objective

This study aimed to evaluate and compare the misclassification of periodontitis using two operational protocols currently employed in research, as a result of intra‐examiner less‐than‐perfect reliability of their formative clinical parameters.

Methods

Full‐mouth duplicate recordings (six sites per tooth) of probing depth (PD) and clinical attachment level (CAL) were obtained by a single examiner, 1 week apart, from 148 adults with self‐perceived need for periodontal treatment. They were used to classify periodontitis subjects according to the protocols proposed by the 5th European Workshop in Periodontology (EWP5) and the collaboration between the US Centre for Diseases Control and Prevention and the American Academy of Periodontology (CDC‐AAP).

Results

Hundred percent and 91.2% of the subjects were classified as periodontitis cases according to the EWP5 and CDC‐AAP protocols, respectively. Test–retest agreement was observed in 95% and 85% of the classified subjects according to the EWP5 and CDC‐AAP protocols, respectively. The difference was statistically significant (P < 0.01). Alignment of protocols, in terms of number of classification categories, resulted in a similar test–retest agreement of 95% using the EWP5 protocol for extensive periodontitis and 90% using the CDC‐AAP protocol for severe periodontitis (P = 0.09). Misclassification was nondifferential when subjects were classified according either to the EWP5 or the aligned CDC‐AAP protocols, while the reliability using the original CDC‐AAP protocol depended on the extent of bleeding on probing, CAL ≥3 mm and PD ≥4 mm.

Conclusion

This study suggests the EWP5 protocol is less error‐prone than the CDC‐AAP protocol in adult subjects with perceived need for periodontal treatment, as a result of intra‐examiner less‐than‐perfect reliability of periodontal clinical parameters. Extensive or severe cases presented similar misclassification. Further studies using survey‐like conditions are recommended to confirm these findings.
Assessing the likely effectiveness of multispecies management for imperiled desert fishes with niche overlap analysis
Authors: Laub Brian G. , Budy Phaedra
Published: January 2015

A critical decision in species conservation is whether to target individual species or a complex of ecologically similar species. Management of multispecies complexes is likely to be most effective when species share similar distributions, threats, and response to threats. We used niche overlap analysis to assess ecological similarity of 3 sensitive desert fish species currently managed as an ecological complex. We measured the amount of shared distribution of multiple habitat and life history parameters between each pair of species. Habitat use and multiple life history parameters, including maximum body length, spawning temperature, and longevity, differed significantly among the 3 species. The differences in habitat use and life history parameters among the species suggest they are likely to respond differently to similar threats and that most management actions will not benefit all 3 species equally. Habitat restoration, frequency of stream dewatering, non‐native species control, and management efforts in tributaries versus main stem rivers are all likely to impact each of the species differently. Our results demonstrate that niche overlap analysis provides a powerful tool for assessing the likely effectiveness of multispecies versus single‐species conservation plans.

Evaluación de la Posible Efectividad del Manejo Multi‐Especie paraPeces de Desierto en Peligro Mediante el Análisis de Traslape de Nichos
Genetic isolation by distance reveals restricted dispersal across a range of life histories: implications for biodiversity conservation planning across highly variable marine environments
Authors: Wright Daniel , Bishop Jacqueline M. , Matthee Conrad A. , von der Heyden Sophie
Published: January 2015

Aim

Isolation by distance (IBD) analyses are an effective tool for determining genetic connectivity among populations, providing a basis for estimating dispersal and thus contributing to spatial biodiversity planning. Here, we use an IBD approach to determine patterns of connectivity to infer dispersal distances for a phylogenetically diverse range of marine species.

Location

Two thousand and eight hundred kilometre of South African coastline.

Methods

mtDNA data sets for 11 rocky shore and reef‐dwelling marine species with diverse life history strategies (broadcast spawning, brooding and live‐bearing) were used to quantify intraspecific genetic connectivity by means of global and pairwise Φst. Mantel tests were used to assess the significance of genetic structure with geographic distance. Significant, positive slopes were used to estimate dispersal distances. For all species, we also plotted genetic diversity along the coast and compared this to patterns of species richness.

Results

For seven of the 11 species tested, we report positive IBD relationships, with patterns of IBD of similar magnitude in broadcast spawners and live‐bearers. Dispersal estimates were low, with effective distances of < 10 km per generation. We find discordance between pelagic larval development and population structure and that genetic structure and the physio‐geographic features of the coastline considered to be important biogeographic barriers do not overlap. Genetic diversity and species richness show congruent patterns, with both variables lowest on the west coast, and increasing towards the east.

Main conclusions

Our study highlights the complexity of marine systems and the clear need for regional assessments of connectivity, rather than more general management plans which may not otherwise effectively encompass area‐specific conservation needs. Importantly, we show that the current marine protected area (MPA) network in South Africa is not effective in protecting evolutionary processes and strongly recommend a network of more closely spaced MPAs in the region that reflects the low average connectivity between distant marine populations.
Randomized comparison trial of density and context of upper limb intensive group versus individualized occupational therapy for children with unilateral cerebral palsy
Authors: Sakzewski Leanne , Miller Laura , Ziviani Jenny , Abbott David F , Rose Stephen , Macdonell Richard A L , Boyd Roslyn N
Published: January 2015

Aim

To determine whether short‐term intensive group‐based therapy combining modified constraint‐induced movement therapy and bimanual therapy (hybrid‐CIMT) is more effective than an equal total dose of distributed individualized occupational therapy (standard care) on upper limb motor and individualized outcomes.

Method

Fifty‐three children with unilateral cerebral palsy (69% males; mean age 7y 10mo, SD 2y 4mo; Manual Ability Classification System level I, n=24; level II, n=23) were randomly allocated, and 44 received either hybrid‐CIMT (n=25) or standard care (n=19). Standard care comprised six weekly occupational therapy sessions and a 12‐week home programme. Outcomes were assessed at baseline, 13 weeks, and 26 weeks after treatment.

Results

Groups were equivalent at baseline. Standard care achieved greater gains on satisfaction with occupational performance after intervention (estimated mean difference −1.2, 95% CI −2.2 to −0.1; p=0.04) and Assisting Hand Assessment at 26 weeks (estimated mean difference 3.1, 95% CI 0.2–6.0; p=0.04). Both groups demonstrated significant improvements in dexterity of the impaired upper limb, and bimanual and occupational performance over time. The differences between groups were not clinically meaningful.

Interpretation

There were no differences between the two models of therapy delivery. Group‐based intensive camps may not be readily available; however, individualized standard care augmented with a home programme may offer an effective alternative but needs to be provided at a sufficient dose.
Service‐Learning in Supply Chain Management: Benefits, Challenges and Best Practices
Authors: Schoenherr Tobias
Published: January 2015

Service‐learning (SL) is a pedagogical approach in which students are assigned a course‐related project in a not‐for‐profit organization, and are tasked to apply course content to execute the project. While the benefits are multifarious, only recently have supply chain management (SCM) courses adapted this innovative teaching methodology. The present article aims to popularize this pedagogical concept by providing a detailed overview of the background, development, implementation, and success of an SL project in an undergraduate SCM course; this serves as a “how to” guide for instructors interested in implementing the approach. Compelling evidence for the value of SL is provided by data assessing the students’ learning experiences, and benefits for participating organizations are demonstrated. Caveats and challenges are noted, and ensuing best practices for SL are presented.
“Supply Chain—Marketing Shark Tank” Experiential Lab Game in Interdisciplinary Business Education: Qualitative and Quantitative Analyses
Authors: Arora A. , Saxena Arora A.
Published: January 2015

This article provides educators in business schools with a new interdisciplinary experiential lab game called Supply Chain—Marketing (SC‐Mark) Shark Tank game, which can be implemented in both Supply Chain Management (SCM) and Marketing courses. The SC‐Mark experiential lab game is a real‐life business environment simulation that explores complexities in advertising industry service supply chains. One hundred sixty‐one undergraduate students participated in the game at two business schools over two semesters. The effectiveness of the game was measured and analyzed, qualitatively and quantitatively, based on text analysis of the feedback received from participating students. The results revealed five themes that helped student teams understand how advertising companies integrate and improve their service supply chains—buyer‐supplier relationships, supply chain functions and operations, consumer focus and orientation, community focus, and overall risk management.
Diagnostic and prognostic value of autoantibodies anti‐apolipoprotein A‐1 and anti‐phosphorylcholine in acute non‐ST elevation myocardial infarction
Authors: Rubini Gimenez Maria , Pagano Sabrina , Virzi Julien , Montecucco Fabrizio , Twerenbold Raphael , Reichlin Tobias , Wildi Karin , Grueter Daniel , Jaeger Cedric , Haaf Philip , Vuilleumier Nicolas , Mueller Christian
Published: January 2015

Background

Autoantibodies have been shown to play a critical role in predicting major adverse cardiovascular events in atherosclerotic patients. We aimed to assess the diagnostic accuracy of autoantibodies to apolipoprotein A‐1 (anti‐apoA‐1 IgG) and to phosphorylcholine (anti‐PC IgM) for non‐ST segment elevation acute myocardial infarction (NSTEMI) and to explore their potential prognostic value.

Methods

This prospective multicentre study included 1072 patients presenting to the emergency department for suspected NSTEMI. The final diagnosis was adjudicated by two independent cardiologists. For both antibodies alone or expressed as a ratio (anti‐apoA‐1 IgG/anti‐PC IgM), we determined their (i) diagnostic accuracy for NSTEMI and (ii) prognostic accuracy for major adverse cardiovascular events (MACE) during 1‐year follow‐up.

Results

A total of 154 patients (14%) had a final diagnosis of NSTEMI. Diagnostic accuracy for the diagnosis of NSTEMI as quantified by the area under the receiver operating characteristics curve (AUC) was very low for both autoantibodies separately as well as combined as a ratio: AUC anti‐apoA‐1 IgG 0·50 (95%CI, 0·47–0·53, P = 0·99), AUC anti‐PC IgM 0·53 (95%CI, 0·50–0·56, P = 0·30) and AUC of the ratio 0·52 (95%CI, 0·49–0·55, P = 0·47). Adding the anti‐apoA‐1 IgG/Anti‐PC IgM ratio to hs‐cTnT did not provide incremental diagnostic value over hs‐cTnT alone. MACE occurred in 221 patients (21%) during follow‐up. The autoantibodies, separately or expressed as ratio, also had very low accuracy to predict MACE (p=ns).

Conclusions

Anti‐apoA‐1 IgG and anti‐PC IgM autoantibodies did not have diagnostic or prognostic value in patients with NSTEMI.
Mutations in Caenorhabditis briggsae identify new genes important for limiting the response to EGF signaling during vulval development
Authors: Sharanya Devika , Fillis Cambree J. , Kim Jaeyoung , Zitnik Edward M. , Ward Kelly A. , Gallagher Molly E. , Chamberlin Helen M. , Gupta Bhagwati P.
Published: January 2015

Studies of vulval development in the nematode C. elegans have identified many genes that are involved in cell division and differentiation processes. Some of these encode components of conserved signal transduction pathways mediated by EGF, Notch, and Wnt. To understand how developmental mechanisms change during evolution, we are doing a comparative analysis of vulva formation in C. briggsae, a species that is closely related to C. elegans. Here, we report 14 mutations in 7 Multivulva (Muv) genes in C. briggsae that inhibit inappropriate division of vulval precursors. We have developed a new efficient and cost‐effective gene mapping method to localize Muv mutations to small genetic intervals on chromosomes, thus facilitating cloning and functional studies. We demonstrate the utility of our method by determining molecular identities of three of the Muv genes that include orthologs of Cel‐lin‐1 (ETS) and Cel‐lin‐31 (Winged‐Helix) of the EGF‐Ras pathway and Cel‐pry‐1 (Axin), of the Wnt pathway. The remaining four genes reside in regions that lack orthologs of known C. elegans Muv genes. Inhibitor studies demonstrate that the Muv phenotype of all four new genes is dependent on the activity of the EGF pathway kinase, MEK. One of these, Cbr‐lin(gu167), shows modest increase in the expression of Cbr‐lin‐3/EGF compared to wild type. These results argue that while Cbr‐lin(gu167) may act upstream of Cbr‐lin‐3/EGF, the other three genes influence the EGF pathway downstream or in parallel to Cbr‐lin‐3. Overall, our findings demonstrate that the genetic program underlying a conserved developmental process includes both conserved and divergent functional contributions.
Aspects of dorso‐ventral and proximo‐distal limb patterning in onychophorans
Authors: Janssen Ralf , Jörgensen Mette , Prpic Nikola‐Michael , Budd Graham E.
Published: January 2015

Onychophorans (velvet worms) are closely related to the arthropods, but their limb morphology represents a stage before arthropodization (i.e., the segmentation of the limbs). We investigated the expression of onychophoran homologs of genes that are involved in dorso‐ventral (DV) and proximo‐distal (PD) limb patterning in arthropods. We find that the two onychophoran optomotor‐blind (omb) genes, omb‐1 and omb‐2, are both expressed in conserved patterns in the dorsal ectoderm of the limbs, including the onychophoran antennae (the frontal appendages). Surprisingly, the expression of decapentaplegic (dpp), which acts upstream of omb in Drosophila, is partially reversed in onychophoran limbs compared to its expression in arthropods. A conserved feature of dpp expression in arthropods and onychophorans, however, is the prominent expression of dpp in the tips of developing limbs, which, therefore, may represent the ancestral pattern. The expression patterns of wingless (wg) and H15 are very diverged in onychophorans. The wg gene is only expressed in the limb tips and the single H15 gene is expressed in a few dorsal limb cells, but not on the ventral side. The expression of wg and dpp at the limb tips is one of the three possible alternatives predicted by the topology model of arthropod limb patterning and is, thus, compatible with a conserved function of wg and dpp in the patterning of the PD axis. On the other hand, DV limb gene expression is less conserved, and the specification of ventral fate appears to involve neither wg nor H15 expression.