bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonessential nucleoporins Nup2, Nup60 and Nup84 are required for normal meiosis inSaccharomyces cerevisiae
Authors: Chu Daniel B. , Burgess Sean M.
Published: May 2016

The nuclear pore complex (NPC) selectively transports cargo between the nucleus and the cytoplasm. The inner nuclear membrane (INM) face of the NPC also serves as a hub where gene silencing and DNA repair are spatially coordinated. InSaccharomyces cerevisiae, partitioning of active and silenced chromatin at subtelomeric regions depends on the boundary activity of nonessential nucleoporin proteins Nup2 and Nup60, along with Htz1, the histone variant H2A.Z. The INM is also important for the chromosome events of meiosis since Ndj1-mediated telomere attachment and clustering at the INM is required for efficient homolog pairing, recombination, and segregation. Here we tested possible meiotic roles for Nup2, Nup60, Htz1, and other nonessential nucleoporins by analyzing the effects of deletion mutations on sporulation, spore viability and possible phenotypic epistasis withndj1Δ. DeletingNUP2,NUP60, andHTZ1reduced spore viability compared to wild-type (WT). A detailed analysis of spore lethality indicated that homolog nondisjunction in these mutants was elevated compared to WT, yet unlikendj1Δ, this was not the predominant cause of spore death. DeletingNUP84reduced meiosis I nuclear divisions, while deletingNUP53,NUP100, andNUP157had no effect on sporulation, spore viability, or the kinetics of meiosis I progression. Surprisingly,nup2Δ ndj1Δuniquely failed to undergo meiosis I nuclear divisions, suggesting Nup2 and Ndj1 function in partially redundant pathways or create a poisonous intermediate. The meiosis I division was also delayed by 2 hours innup2Δcompared to WT pointing to a specialized role for Nup2 in the meiotic program.
Improving occupational health by modelling indoor pollutant distribution
Authors: Pitarma Rui , Lourenço Miguel , Ramos João
Published: May 2016

Purpose

Indoor environments are characterized by several pollutant sources. Some of these can be sufficiently characterized through the prediction of the airflow and pollutant distribution patterns. The purpose of this study was to simulate, analyze and compare different locations of known pollutant source inside a ventilated room.

Design/methodology/approach

Computational fluid dynamics modelling approach was used to analyze the prediction of the airflow and pollutant distribution patterns for different locations of known pollutant source inside a ventilated room by mixing ventilation.

Findings

Distinct areas of poor air quality, perfectly identified by concentration fields, were given. The indoor air quality obtained by the different simulated conditions was analyzed and compared.

Research limitations/implications

Pollutant concentration was not measured in the validation experiments (qualitative validation based on the velocity fields).

Practical implications

Once the contaminant concentration fields are calculated based on the source location, the model is very useful to choose the best place to install any pollutant indoor equipment to preserve breathing zones.

Originality/value

Providing an effective indoor air quality assessment to prevent exposure risk. The results would be useful for making decisions to optimize the design procedure, such as establish the best location to install polluting equipment, occupied areas and their interdependence with ventilation systems. In addition, this tool also helps to choose the best location and correct set point adjustment for the pollutant sensors.
Sustainable healthcare design
Authors: Sagha Zadeh Rana , Xuan Xiaodong , Shepley Mardelle M.
Published: May 2016

Purpose

Healthcare projects face multiple obstacles in achieving sustainability. This paper aims to provide information regarding the energy consumption of healthcare facilities, to identify barriers to sustainability and to suggest methods to improve the effectiveness of these buildings.

Design/methodology/approach

This study investigates sustainability in healthcare buildings by examining national databases about energy use and energy savings. The authors then initiate a dialogue on this topic by interviewing experts in healthcare planning and design regarding the implications of this data, challenges to sustainability and potential solutions to these challenges.

Findings

An analysis of data from the Energy Information Administration revealed that healthcare facilities rank second among building types in the USA in energy use per square foot and rank fourth in total energy use. Data from the US Green Building Council showed that only 1 per cent of healthcare buildings are registered with the Leadership in Energy and Environmental Design rating system, and 0.4 per cent have achieved certification, which is low compared with other building types.

Research limitations/implications

Research and discussion must continue engaging all stakeholders to interpret the data and identify transformative solutions to facilitate sustainable healthcare design construction and operation.

Practical implications

It is important to approach sustainability in healthcare from social, economic, environmental and health-related perspectives. The authors identify five major barriers to sustainable healthcare design and construction and discuss 12 practical solutions.

Originality/value

Given the energy demands of healthcare buildings, facilitating their sustainability has the potential to make a significant difference in national energy use. Empirical research and evidence-based design can potentially help to accelerate sustainability by clarifying impacts and documenting the economic and operational returns on investment.
The Free Basics (of Facebook) debate in India
Authors: Tripuraneni Hanuman Chowdary
Published: May 2016

Purpose

This paper aims to dispel and rebut an ideology inspired onslaught on Facebook’s offering of Free Basics, an Internet service described as free to enable the poor to get on to the Internet.

Design/methodology/approach

The study is based on a comparison of Free Basics with several freely and selectively offered goods and services by the government of India and its companies and departments to help the poor.

Findings

Free Basics offered by Facebook is not anti-net neutrality nor discriminatory against innovative service offerings by start-ups or others.

Originality/value

The paper sdds to the material for consideration by the Telecom Regulatory Authority of India in determining its position on the issue.
Process landscape and efficiency in non-life insurance claims management
Authors: Mahlow Nils , Wagner Joël
Published: May 2016

Purpose

In view of the fact that claim payouts account for about 70 per cent of annual direct costs in non-life insurance companies and that claims-handling staff sums up to 10-20 per cent of all employees, an optimal claims management environment is of strategic importance. The purpose of this paper is twofold, i.e. on the one hand, the authors introduce a standardized claims management process model and, on the other hand, they apply process benchmarks to various operational parameters.

Design/methodology/approach

The proposed claims management process landscape comprises current industry standards for claims handling from a theoretical perspective, supported by practice insights from the industry. Our model aims to reflect the most important claims processing activities. The claims-handling work flow is structured into five core steps, namely, notification, registration, coverage audit, settlement and closing of the claim. For these core steps, the authors differentiate between three claim complexity categories and their associated back-office levels. In the second part of the paper, the authors assess the industry’s claims-handling efficiency. The authors benchmark industry processes with reference to detailed claims management data from 11 insurers in Germany and Switzerland.

Findings

The benchmarks are based on the previously defined claims management model and are applied separately to the three retail business lines of car, property and liability insurance. We measure claim process times (cycle times) as well as claim quantities and average claim payouts at different levels. Overall, within each business line, more than 30 data points are gathered from each respondent insurer. This allows us to compare the process performance of different insurance companies and to describe significant differences in their process patterns. Furthermore, principal findings are derived from descriptive statistics as well as ad hoc data analyses.

Originality/value

The paper seeks to contribute to the discussion of how different insurance companies perform in claims management and to define best practice. Our findings are relevant to academics and practitioners alike.
Soil‐mediated eco‐evolutionary feedbacks in the invasive plant Alliaria petiolata
Authors: Evans Jeffrey A. , Lankau Richard A. , Davis Adam S. , Raghu S. , Landis Douglas A.
Published: May 2016

Ecological and evolutionary processes historically have been assumed to operate on significantly different time‐scales. We know now from theory and work in experimental and model systems that these processes can feed back on each other on mutually relevant time‐scales.

Here, we present evidence of a soil‐mediated eco‐evolutionary feedback on the population dynamics of an invasive biennial plant, Alliaria petiolata.

As populations age, natural selection drives down production of A. petiolata's important antimycorrhizal allelochemical, sinigrin. This occurs due to density‐dependent selection on sinigrin, which is favoured under interspecific, but disfavoured under intraspecific, competition.

We show that population stochastic growth rates (λS) and plant densities are positively related to sinigrin concentration measured in seedling roots. This interaction is mediated by sinigrin's positive effect on seedling and summer survival, which are important drivers of λS.

Together, these illustrate how the evolution of a trait shaped by natural selection can influence the ecology of a species over a period of just years to decades, altering its trajectory of population growth and interactions with the species in the soil and plant communities it invades.

Our findings confirm the predictions that eco‐evolutionary feedbacks occur in natural populations. Furthermore, they improve our conceptual framework for projecting future population growth by linking the variation in plant demography to a critical competitive trait (sinigrin) whose selective advantages decrease as populations age.
Prospective evaluation of 68Gallium‐prostate‐specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer
Authors: van Leeuwen Pim J. , Emmett Louise , Ho Bao , Delprado Warick , Ting Francis , Nguyen Quoc , Stricker Phillip D.
Published: May 2016

Objectives

To assess the accuracy of 68Gallium‐prostate‐specific membrane antigen (68Ga‐PSMA) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging in intermediate‐ and high‐risk prostate cancer (PCa).

Materials and Methods

From April to October 2015, 30 patients with intermediate‐ (n = 3) or high‐risk (n = 27) PCa were prospectively enrolled. Patients underwent preoperative 68Ga‐PSMA PET/CT. Both visual and semi‐quantitative analyses were undertaken. Subsequently, all patients underwent radical prostatectomy (RP) with an extended pelvic lymph node dissection. The sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for LN status of 68Ga‐PSMA were calculated using histopathology as reference.

Results

Eleven patients (37%) had lymph node metastases (LNMs); 26 LNMs were identified in the 11 patients. Patient analysis showed that 68Ga‐PSMA PET/CT had a sensitivity of 64% for the detection of LNMs, its specificity was 95%, the PPV was 88%, and the NPV was 82%. In total, 180 LN fields were analysed. In the LN‐region‐based analysis, the sensitivity of 68Ga‐PSMA PET/CT for detection of LNMs was 56%, the specificity was 98%, the PPV was 90% and the NPV was 94%. The mean size of missed LNMs was 2.7 mm. Receiver‐operating characteristic curve analysis showed a high accuracy of maximum standardized uptake value (SUVmax) for the detection of LNMs, with an area under the curve of 0.915 (95% confidence interval 0.847–0.983); the optimum SUVmax was 2.0.

Conclusions

In patients with intermediate‐ to high‐risk PCa, 68Ga‐PSMA PET/CT had a high specificity and a moderate sensitivity for LNM detection. 68Ga‐PSMA PET/CT had the potential to replace current imaging for LN staging of patients with PCa scheduled for RP.
Bone augmentation at peri‐implant dehiscence defects comparing a synthetic polyethylene glycol hydrogel matrix vs. standard guided bone regeneration techniques
Authors: Thoma Daniel S. , Jung Ui‐Won , Park Jin‐Young , Bienz Stefan P. , Hüsler Jürg , Jung Ronald E.
Published: May 2016

Objectives

The aim of the study was to test whether or not the use of a polyethylene glycol (PEG) hydrogel with or without the addition of an arginylglycylaspartic acid (RGD) sequence applied as a matrix in combination with hydroxyapatite/tricalciumphosphate (HA/TCP) results in similar peri‐implant bone regeneration as traditional guided bone regeneration procedures.

Material and methods

In 12 beagle dogs, implant placement and peri‐implant bone regeneration were performed 2 months after tooth extraction in the maxilla. Two standardized box‐shaped defects were bilaterally created, and dental implants were placed in the center of the defects with a dehiscence of 4 mm. Four treatment modalities were randomly applied: i)HA/TCP mixed with a synthetic PEG hydrogel, ii)HA/TCP mixed with a synthetic PEG hydrogel supplemented with an RGD sequence, iii)HA/TCP covered with a native collagen membrane (CM), iv)and no bone augmentation (empty). After a healing period of 8 or 16 weeks, micro‐CT and histological analyses were performed.

Results

Histomorphometric analysis revealed a greater relative augmented area for groups with bone augmentation (43.3%–53.9% at 8 weeks, 31.2%–42.8% at 16 weeks) compared to empty controls (22.9% at 8 weeks, 1.1% at 16 weeks). The median amount of newly formed bone was greatest in group CM at both time‐points. Regarding the first bone‐to‐implant contact, CM was statistically significantly superior to all other groups at 8 weeks.

Conclusions

Bone can partially be regenerated at peri‐implant buccal dehiscence defects using traditional guided bone regeneration techniques. The use of a PEG hydrogel applied as a matrix mixed with a synthetic bone substitute material might lack a sufficient stability over time for this kind of defect.
Direct current stimulation of prefrontal cortex modulates error‐induced behavioral adjustments
Authors: Mansouri Farshad A. , Fehring Daniel J. , Feizpour Azadeh , Gaillard Alexandra , Rosa Marcello G.P. , Rajan Ramesh , Jaberzadeh Shapour
Published: May 2016

Commission of errors and conflict between choices might induce behavioral modulations through adjustments in the executive control of behavior and altered patterns of these modulations are detected in neuropsychiatric disorders. We examined the effects of transcranial Direct Current Stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) on error‐ and conflict‐induced behavioral modulations. Two separate cohorts of participants performed two clinically relevant tests of executive control, respectively. In the Wisconsin Card Sorting Test (WCST), the relevant rule for matching items frequently changed and therefore participants had to detect these unannounced changes by trial and error and alter their rule‐based behavior. In the Stop task, participants had to rapidly respond to a directional go‐signal but inhibit their responses when a stop signal appeared after the go‐signal. Each participant received tDCS (sham, cathodal or anodal) in three separate sessions. Errors led to a slower response in the next trial (post‐error slowing) in both tasks. The tDCS significantly modulated the post‐error slowing in both tasks but did not affect the behavioral adjustments induced by the conflict. The modulation of post‐error slowing by tDCS were polarity‐dependent and also trial specific appearing immediately after errors. In the WCST and Stop task, the post‐error slowing may reflect different processes involved in shifting the behavior‐guiding rule and adjustments in inhibitory control of responses, respectively, and we found that the effective tDCS polarity differed between the two tasks. Here, we show that in two separate cognitive tasks direct current stimulation of DLPFC significantly modulated error‐induced behavioral modulations.
The segmental diffusivity profile of amyotrophic lateral sclerosis associated white matter degeneration
Authors: Schuster C. , Elamin M. , Hardiman O. , Bede P.
Published: May 2016

Background and purpose

Magnetic resonance diffusivity indices have been repeatedly proposed as biomarkers of neurodegeneration in amyotrophic lateral sclerosis (ALS), but no consensus exists as to which diffusivity parameter is the most sensitive to identify early degenerative changes. Despite numerous studies, surprisingly little is known of the segmental vulnerability of the corticospinal tracts and corpus callosum. Our objective was to characterize the core three‐dimensional white matter signature of ALS, to describe phenotype‐specific patterns of white matter degeneration and to evaluate the diffusivity profile of individual patients and controls in specific white matter segments.

Methods

A large neuroimaging study was undertaken with 62 patients and 55 age‐matched healthy controls. White matter alterations were explored based on fractional anisotropy and radial, mean and axial diffusivity indices. Atlas‐based region of interest analyses were carried out in the corona radiata, internal capsules, cerebral peduncles, and in the splenium, body and genu of the corpus callosum. Percentage change and receiver operating characteristic (ROC) curves were used to characterize disease‐state discriminating diffusivity measures and white matter regions.

Results

Bulbar onset patients exhibit extensive corticobulbar tract involvement in the genu of the internal capsule and in the lateral fibres of the corona radiata subjacent to the bulbar representation of the motor homunculus. Spinal onset patients show predominantly posterior internal capsule involvement and medial corona radiata pathology. ROC curve analyses revealed that diffusivity measures of the cerebral crura best discriminate patients and controls (area under the curve 80.1%).

Conclusions

Amyotrophic lateral sclerosis is associated with a core, disease‐specific three‐dimensional white matter signature which is best demonstrated by radial diffusivity measurements. The main ALS motor phenotypes are manifestations of the relatively selective involvement of corticospinal and corticobulbar fibres.
Fatal hepatocellular carcinoma presenting with oral metastasis in a patient with synchronic primary malignancies of prostate and liver
Authors: Rodrigues Maria Fernanda Setúbal Destro , Esteves Carina Magalhães , de Oliveira Márcio Augusto , de Andrade Nathália Paiva , Sedassari Bruno Tavares , Soares Fernando Augusto , Nunes Fabio Daumas
Published: May 2016

Background

Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer and its occurrence in the oral cavity as a metastatic neoplasm is a rare event. We describe a fatal case of HCC with oral metastasis in a patient firstly diagnosed with prostatic and hepatic carcinomas. The histopathological examination revealed a hepatocyte‐like tumour cells arranged in organoid structures as well as positivity to cytokeratin 8 and Hep Par 1. The present findings highlight the importance of a complete medical evaluation of the patient to identify possible oral repercussions of primary diseases.
Typecasts, Tokens, and Spokespersons: A Case for Credibility Excess as Testimonial Injustice
Authors: Davis Emmalon
Published: May 2016

Miranda Fricker maintains that testimonial injustice is a matter of credibility deficit, not excess. In this article, I argue that this restricted characterization of testimonial injustice is too narrow. I introduce a type of identity‐prejudicial credibility excess that harms its targets qua knowers and transmitters of knowledge. I show how positive stereotyping and prejudicially inflated credibility assessments contribute to the continued epistemic oppression of marginalized knowers. In particular, I examine harms such as typecasting, compulsory representation, and epistemic exploitation and consider what hearers are obligated to do in response to these injustices. I argue that because epistemic harms to marginalized knowers also arise from prejudicially inflated assessments of their credibility, the virtue of testimonial justice must be revised to remedy them.
Formation of electrostatic complexes using sodium caseinate with high‐methoxyl pectin and carboxymethyl cellulose and their application in stabilisation of curcumin
Authors: Cho Hyunnho , Jung Hana , Lee HeeJae , Kwak Ho‐Kyung , Hwang Keum Taek
Published: May 2016

Despite many reported bioactivities of curcumin, its application is limited due to its low bioavailability, solubility and stability. Proteins have been reported to stabilise curcumin in aqueous media, and stabilisation of curcumin could be enhanced when proteins form an electrostatic complex with polysaccharides. In this study, electrostatic complexes of sodium caseinate (NaCas) were prepared using high‐methoxyl pectin (HMP and NaCas‐HMP) and carboxymethyl cellulose (CMC and NaCas‐CMC). NaCas to polysaccharide ratio of 1:2 resulted in the lowest turbidity and sedimentation. The electrostatic complexes were more stable than native NaCas against pH change and ionic strength. Binding of curcumin to NaCas and the electrostatic complexes were confirmed by UV‐vis and fluorescence spectra and Fourier transform infrared spectroscopy (FT‐IR). The electrostatic complexes showed a higher binding constant and protected curcumin better than the native NaCas. This study suggests that the electrostatic complexes may be a superior carrier to NaCas at an acidic environment.
A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity
Authors: Rogers Jack T. , Venkataramani Vivek , Washburn Cecilia , Liu Yanyan , Tummala Vinusha , Jiang Hong , Smith Ann , Cahill Catherine M.
Published: May 2016

Iron supplementation ameliorates the neurotoxicity of the environmental contaminant lead (Pb); however, the mechanism remains undefined. Iron is an essential nutrient but high levels are toxic due to the catalytic generation of destructive hydroxyl radicals. Using human neuroblastoma SH‐SY5Y cells to model human neurons, we investigated the effect of Pb on proteins of iron homeostasis: the Alzheimer's amyloid precursor protein (APP), which stabilizes the iron exporter ferroportin 1; and, the heavy subunit of the iron‐storage protein, ferritin (FTH). Lead (Pb(II) and Pb(IV) inhibited APP translation and raised cytosolic iron(II). Lead also increased iron regulatory protein‐1 binding to the cognate 5′untranslated region‐specific iron‐responsive element (IRE) of APP and FTH mRNAs. Concurrent iron treatment rescued cells from Pb toxicity by specifically restoring APP synthesis, i.e. levels of the APP‐related protein, APLP‐2, were unchanged. Significantly, iron/IRE‐independent over‐expression of APP695 protected SH‐SY5Y cells from Pb toxicity, demonstrating that APP plays a key role in maintaining safe levels of intracellular iron. Overall, our data support a model of neurotoxicity where Pb enhances iron regulatory protein/IRE‐mediated repression of APP and FTH translation. We propose novel treatment options for Pb poisoning to include chelators and the use of small molecules to maintain APP and FTH translation.

image

We propose the following cascade for Lead (Pb) toxicity to neurons; by targeting the interaction between Iron regulatory protein‐1 and Iron‐responsive elements, Pb caused translational repression of proteins that control intracellular iron homeostasis, including the Alzheimer's amyloid precursor protein (APP) that stabilizes the iron exporter ferroportin, and the ferroxidase heavy subunit of the iron‐storage protein, ferritin. When unregulated, IRE‐independent over‐expression of APP695 protected SH‐SY5Y neurons from Pb toxicity. There is a novel and key role for APP in maintaining safe levels of intracellular iron pertinent to lead toxicity.
Interplay of enzymatic and structural functions of CaMKII in long‐term potentiation
Authors: Kim Karam , Saneyoshi Takeo , Hosokawa Tomohisa , Okamoto Kenichi , Hayashi Yasunori
Published: May 2016

Since the discovery of long‐term potentiation (LTP) about a half‐century ago, Ca2+/CaM‐dependent protein kinase II (CaMKII) has been one of the most extensively studied components of the molecular machinery that regulate plasticity. This unique dodecameric kinase complex plays pivotal roles in LTP by phosphorylating substrates through elaborate regulatory mechanisms, and is known to be both necessary and sufficient for LTP. In addition to acting as a kinase, CaMKII has been postulated to have structural roles because of its extraordinary abundance and diverse interacting partners. It now is becoming clear that these two functions of CaMKII cooperate closely for the induction of both functional and structural synaptic plasticity of dendritic spines.

image

Because of its extraordinary abundance within neuronal cells, calmodulin kinase CaMKII has been believed to act as a structural protein as well as an enzyme during synaptic plasticity. In this review, we summarized studies in CaMKII field and provide an insight into how enzymatic and structural functions of CaMKII cooperate with each other for long‐term potentiation (LTP) in neurons.

This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
The evolution of genomic islands by increased establishment probability of linked alleles
Authors: Yeaman Sam , Aeschbacher Simon , Bürger Reinhard
Published: May 2016

Genomic islands are clusters of loci with elevated divergence that are commonly found in population genomic studies of local adaptation and speciation. One explanation for their evolution is that linkage between selected alleles confers a benefit, which increases the establishment probability of new mutations that are linked to existing locally adapted polymorphisms. Previous theory suggested there is only limited potential for the evolution of islands via this mechanism, but involved some simplifying assumptions that may limit the accuracy of this inference. Here, we extend previous analytical approaches to study the effect of linkage on the establishment probability of new mutations and identify parameter regimes that are most likely to lead to evolution of islands via this mechanism. We show how the interplay between migration and selection affects the establishment probability of linked vs. unlinked alleles, the expected maximum size of genomic islands, and the expected time required for their evolution. Our results agree with previous studies, suggesting that this mechanism alone is unlikely to be a general explanation for the evolution of genomic islands. However, this mechanism could occur more readily if there were other pre‐adaptations to reduce local rates of recombination or increase the local density of mutational targets within the region of the island. We also show that island formation via erosion following secondary contact is much more rapid than island formation from de novo mutations, suggesting that this mechanism may be more likely.
Cross-Validatory Extreme Value Threshold Selection and Uncertainty with Application to Ocean Storm Severity
Authors: Northrop Paul J. , Attalides Nicolas , Jonathan Philip
Published: May 2016

Design conditions for marine structures are typically informed by threshold-based extreme value analyses of oceanographic variables, in which excesses of a high threshold are modelled by a generalized Pareto distribution. Too low a threshold leads to bias from model misspecification, and raising the threshold increases the variance of estimators: a bias–variance trade-off. Many existing threshold selection methods do not address this trade-off directly but rather aim to select the lowest threshold above which the generalized Pareto model is judged to hold approximately. In the paper Bayesian cross-validation is used to address the trade-off by comparing thresholds based on predictive ability at extreme levels. Extremal inferences can be sensitive to the choice of a single threshold. We use Bayesian model averaging to combine inferences from many thresholds, thereby reducing sensitivity to the choice of a single threshold. The methodology is applied to significant wave height data sets from the northern North Sea and the Gulf of Mexico.
Balancing the Evidence: How to Reconcile the Results of Observational Studies vs. Randomized Clinical Trials in Dialysis
Authors: Shen Jenny I. , Lum Erik L. , Chang Tara I.
Published: May 2016

Because large randomized clinical trials (RCTs) in dialysis have been relatively scarce, evidence‐based dialysis care has depended heavily on the results of observational studies. However, when results from RCTs appear to contradict the findings of observational studies, nephrologists are left to wonder which type of study they should believe. In this editorial, we explore the key differences between observational studies and RCTs in the context of such seemingly conflicting studies in dialysis. Confounding is the major limitation of observational studies, whereas low statistical power and problems with external validity are more likely to limit the findings of RCTs. Differences in the specification of the population, exposure, and outcomes can also contribute to different results among RCTs and observational studies. Rigorous methods are required regardless of what type of study is conducted, and readers should not automatically assume that one type of study design is superior to the other. Ultimately, dialysis care requires both well‐designed, well‐conducted observational studies and RCTs to move the field forward.
Density of potentially crystalline representations of fixed weight
Authors: Hellmann Eugen , Schraen Benjamin
Published: May 2016

Let $K$ be a finite extension of $\mathbb{Q}_{p}$ and let $\bar{\unicode[STIX]{x1D70C}}$ be a continuous, absolutely irreducible representation of its absolute Galois group with values in a finite field of characteristic $p$. We prove that the Galois representations that become crystalline of a fixed regular weight after an abelian extension are Zariski-dense in the generic fiber of the universal deformation ring of $\bar{\unicode[STIX]{x1D70C}}$. In fact we deduce this from a similar density result for the space of trianguline representations. This uses an embedding of eigenvarieties for unitary groups into the spaces of trianguline representations as well as the corresponding density claim for eigenvarieties as a global input.
Multilocus Sequence Typing of Pathogenic Treponemes Isolated from Cloven-Hoofed Animals and Comparison to Treponemes Isolated from Humans
Authors: Clegg Simon R. , Carter Stuart D. , Birtles Richard J. , Brown Jennifer M. , Hart C. Anthony , Evans Nicholas J.
Published: May 2016

Treponema
species are implicated in many diseases of humans and animals. Digital dermatitis (DD) treponemes are reported to cause severe lesions in cattle, sheep, pigs, goats, and wild elk, causing substantial global animal welfare issues and economic losses. The fastidiousness of these spirochetes has previously precluded studies investigating within-phylogroup genetic diversity. An archive of treponemes that we isolated enabled multilocus sequence typing to quantify the diversity and population structure of DD treponemes. Isolates (
n
= 121) were obtained from different animal hosts in nine countries on three continents. The analyses herein of currently isolated DD treponemes at seven housekeeping gene loci confirm the classification of the three previously designated phylogroups: the
Treponema medium
,
Treponema phagedenis
, and
Treponema pedis
phylogroups. Sequence analysis of seven DD treponeme housekeeping genes revealed a generally low level of diversity among the strains within each phylogroup, removing the need for the previously used “-like” suffix. Surprisingly, all isolates within each phylogroup clustered together, regardless of host or geographic origin, suggesting that the same sequence types (STs) can infect different animals. Some STs were derived from multiple animals from the same farm, highlighting probable within-farm transmissions. Several STs infected multiple hosts from similar geographic regions, identifying probable frequent between-host transmissions. Interestingly,
T. pedis
appears to be evolving more quickly than the
T. medium
or
T. phagedenis
DD treponeme phylogroup, by forming two unique ST complexes. The lack of phylogenetic discrimination between treponemes isolated from different hosts or geographic regions substantially contrasts with the data for other clinically relevant spirochetes.

IMPORTANCE
The recent expansion of the host range of digital dermatitis (DD) treponemes from cattle to sheep, goats, pigs, and wild elk, coupled with the high level of 16S rRNA gene sequence similarity across hosts and with human treponemes, suggests that the same bacterial species can cause disease in multiple different hosts. This multilocus sequence typing (MLST) study further demonstrates that these bacteria isolated from different hosts are indeed very similar, raising the potential for cross-species transmission. The study also shows that infection spread occurs frequently, both locally and globally, suggesting transmission by routes other than animal-animal transmission alone. These results indicate that on-farm biosecurity is important for controlling disease spread in domesticated species. Continued surveillance and vigilance are important for ascertaining the evolution and tracking any further host range expansion of these important pathogens.
Novel
P450nor
Gene Detection Assay Used To Characterize the Prevalence and Diversity of Soil Fungal Denitrifiers
Authors: Novinscak Amy , Goyer Claudia , Zebarth Bernie J. , Burton David L. , Chantigny Martin H. , Filion Martin
Published: May 2016

Denitrifying fungi produce nitrous oxide (N
2
O), a potent greenhouse gas, as they generally lack the ability to convert N
2
O to dinitrogen. Contrary to the case for bacterial denitrifiers, the prevalence and diversity of denitrifying fungi found in the environment are not well characterized. In this study, denitrifying fungi were isolated from various soil ecosystems, and novel PCR primers targeting the
P450nor
gene, encoding the enzyme responsible for the conversion of nitric oxide to N
2
O, were developed, validated, and used to study the diversity of cultivable fungal denitrifiers. This PCR assay was also used to detect
P450nor
genes directly from environmental soil samples. Fungal denitrification capabilities were further validated using an N
2
O gas detection assay and a PCR assay targeting the
nirK
gene. A collection of 492 facultative anaerobic fungi was isolated from 15 soil ecosystems and taxonomically identified by sequencing the internal transcribed spacer sequence. Twenty-seven fungal denitrifiers belonging to 10 genera had the
P450nor
and the
nirK
genes and produced N
2
O from nitrite. N
2
O production is reported in strains not commonly known as denitrifiers, such as
Byssochlamys nivea
,
Volutella ciliata
,
Chloridium
spp., and
Trichocladium
spp. The prevalence of fungal denitrifiers did not follow a soil ecosystem distribution; however, a higher diversity was observed in compost and agricultural soils. The phylogenetic trees constructed using partial
P450nor
and
nirK
gene sequences revealed that both genes clustered taxonomically closely related strains together.

IMPORTANCE
A PCR assay targeting the
P450nor
gene involved in fungal denitrification was developed and validated. The newly developed
P450nor
primers were used on fungal DNA extracted from a collection of fungi isolated from various soil environments and on DNA directly extracted from soil. The results indicated that approximatively 25% of all isolated fungi possessed this gene and were able to convert nitrite to N
2
O. All soil samples from which denitrifying fungi were isolated also tested positive for the presence of
P450nor
. The
P450nor
gene detection assay was reliable in detecting a large diversity of fungal denitrifiers. Due to the lack of homology existing between
P450nor
and bacterial denitrification genes, it is expected that this assay will become a tool of choice for studying fungal denitrifiers.
Loss of SigB in Listeria monocytogenes Strains EGD-e and 10403S Confers Hyperresistance to Hydrogen Peroxide in Stationary Phase under Aerobic Conditions
Authors: Boura Marcia , Keating Ciara , Royet Kevin , Paudyal Ranju , O'Donoghue Beth , O'Byrne Conor P. , Karatzas Kimon A. G.
Published: May 2016

SigB is the main stress gene regulator in
Listeria monocytogenes
affecting the expression of more than 150 genes and thus contributing to multiple-stress resistance. Despite its clear role in most stresses, its role in oxidative stress is uncertain, as results accompanying the loss of
sigB
range from hyperresistance to hypersensitivity. Previously, these differences have been attributed to strain variation. In this study, we show conclusively that unlike for all other stresses, loss of
sigB
results in hyperresistance to H
2
O
2
(more than 8 log CFU ml
−1
compared to the wild type) in aerobically grown stationary-phase cultures of
L. monocytogenes
strains 10403S and EGD-e. Furthermore, growth at 30°C resulted in higher resistance to oxidative stress than that at 37°C. Oxidative stress resistance seemed to be higher with higher levels of oxygen. Under anaerobic conditions, the loss of SigB in 10403S did not affect survival against H
2
O
2
, while in EGD-e, it resulted in a sensitive phenotype. During exponential phase, minor differences occurred, and this result was expected due to the absence of
sigB
transcription. Catalase tests were performed under all conditions, and stronger catalase results corresponded well with a higher survival rate, underpinning the important role of catalase in this phenotype. Furthermore, we assessed the catalase activity in protein lysates, which corresponded with the catalase tests and survival. In addition, reverse transcription-PCR (RT-PCR) showed no differences in transcription between the wild type and the Δ
sigB
mutant in various oxidative stress genes. Further investigation of the molecular mechanism behind this phenotype and its possible consequences for the overall phenotype of
L. monocytogenes
are under way.

IMPORTANCE
SigB is the most important stress gene regulator in
L. monocytogenes
and other Gram-positive bacteria. Its increased expression during stationary phase results in resistance to multiple stresses. However, despite its important role in general stress resistance, its expression is detrimental for the cell in the presence of oxidative stress, as it promotes hypersensitivity against hydrogen peroxide. This peculiar phenotype is an important element of the physiology of
L. monocytogenes
, and it might help us explain the behavior of this organism in environments where oxidative stress is present.
Stick-split mechanism for anthropogenic fluid-induced tensile rock failure
Authors: van der Baan Mirko , Eaton David W. , Preisig Giona
Published: May 2016

Fluids play a critical role in natural and human-induced rock failure. It is unclear, however, if propagation of a tensile fracture is inherently an episodic or continuous process. For example, typical average propagation speeds of hydraulic fracture tips on the order of 1–10 m/min suggest continuous crack growth, possibly at subcritical stress intensities. In contrast, using field observations and numerical and mathematical analyses, we show that fracture growth due to anthropogenic hydraulic fracturing is most likely to occur in an episodic fashion, characterized by stick-split behavior that is analogous to stick-slip motion of earthquakes. The stick-split mechanism is regulated by cyclic variations in fluid pressure near the crack tip, in which each successive failure produces a local pressure drop that temporarily halts or slows fracture propagation. A pressure drop results in partial fracture closure, producing noncontinuous fracture propagation through a process that is reminiscent of hand clapping. Rupture speeds for individual failure events are on the order of the shear-wave velocity of the medium; thus, continuous crack growth is not a likely mechanism for anthropogenic hydraulic fracturing treatments despite slow average tip propagation speeds.
‘The nice thing about doctors is that you can sometimes get a day off school’: an action research study to bring lived experiences from children, parents and hospice staff into medical students' preparation for practice
Authors: Spalding Jessica , Yardley Sarah
Published: May 2016

Patient and public involvement in healthcare is important to ensure services meet their needs and priorities. Increasingly, patient experiences are being used to educate healthcare professionals. The potential contribution to medical education of children and parents using hospice services has not yet been fully explored.

Objectives

(1) To explore perceptions of what medical students must learn to become ‘good doctors’ among children, parents and staff in a hospice. (2) To collaborate with children/parents and staff to develop educational materials based on their lived experiences for medical students. (3) To assess feasibility of student-led action research in a children's hospice to develop research skills.

Methods

Prospective ethical approval received. Volunteer children (n=7), parents (n=5) and staff (n=6) were recruited from a children's hospice. Data were generated in audio-recorded semistructured focus groups, individual interviews and/or activity workshops. Participants discussed what newly qualified doctors’ needed to care for children with life-limiting conditions. Audio data were transcribed and combined with visual data for thematic analysis. Findings were refined by participant feedback. This paper presents thematic findings and educational material created from the project.

Results

Thematic analysis identified six learning themes: (1) treat children as individuals; (2) act as a person before being a doctor; (3) interpersonal communication; (4) appreciate the clinical environment; (5) learn from children, parents and other staff; (6) how to be a doctor as part of a team. The student researcher successfully developed qualitative research skills, coproducing materials with participants for sharing learning derived from lived experiences.

Conclusions

All participants were willing and able to make valuable contributions, and believed that this was a worthwhile use of time and effort. Further work is required to understand how best to integrate the experiences of children in hospices into medical education.
Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats
Authors: Chapleau Mark W. , Rotella Diane L. , Reho John J. , Rahmouni Kamal , Stauss Harald M.
Published: May 2016

Parasympathetic activity is often reduced in hypertension and can elicit anti-inflammatory mechanisms. Thus we hypothesized that chronic vagal nerve stimulation (VNS) may alleviate cardiovascular end-organ damage in stroke-prone spontaneously hypertensive rats. Vagal nerve stimulators were implanted, a high-salt diet initiated, and the stimulators turned on (VNS, n = 10) or left off (sham, n = 14) for 4 wk. Arterial pressure increased equally in both groups. After 4 wk, endothelial function, assessed by in vivo imaging of the long posterior ciliary artery (LPCA) after stimulation (pilocarpine) and inhibition ( Nω-nitro-l-arginine methyl ester) of endothelial nitric oxide synthase (eNOS), had significantly declined (−2.3 ± 1.2 μm, P < 0.05) in sham, but was maintained (−0.7 ± 0.8 μm, nonsignificant) in VNS. Furthermore, aortic eNOS activation (phosphorylated to total eNOS protein content ratio) was greater in VNS (0.83 ± 0.07) than in sham (0.47 ± 0.08, P < 0.05). After only 3 wk, ultrasound imaging of the aorta demonstrated decreased aortic strain (−9.7 ± 2.2%, P < 0.05) and distensibility (−2.39 ± 0.49 1,000/mmHg, P < 0.05) and increased pulse-wave velocity (+2.4 ± 0.7 m/s, P < 0.05) in sham but not in VNS (−3.8 ± 3.8%, −0.70 ± 1.4 1,000/mmHg, and +0.1 ± 0.7 m/s, all nonsignificant). Interleukin (IL)-6 serum concentrations tended to be higher in VNS than in sham (34.3 ± 8.3 vs. 16.1 ± 4.6 pg/ml, P = 0.06), and positive correlations were found between NO-dependent relaxation of the LPCA and serum levels of IL-6 ( r = +0.70, P < 0.05) and IL-10 (r = +0.56, P < 0.05) and between aortic eNOS activation and IL-10 ( r = +0.48, P < 0.05). In conclusion, chronic VNS prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. We speculate that anti-inflammatory mechanisms may contribute to these effects.

Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/chronic-vagal-nerve-stimulation-in-stroke-prone-shr/ .
MMP-9 signaling in the left ventricle following myocardial infarction
Authors: Iyer Rugmani Padmanabhan , Jung Mira , Lindsey Merry L.
Published: May 2016

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve both the stimulation of robust inflammation to clear necrotic myocytes and tissue debris and the induction of extracellular matrix (ECM) protein synthesis to generate an infarct scar. The collective changes in myocardial structure and function are termed LV remodeling, and matrix metalloproteinase-9 (MMP-9) is a key instigator of post-MI LV remodeling. Through direct molecular effects on ECM and inflammatory protein turnover as well as indirect effects on major cell types that coordinate cardiac wound healing, namely the infiltrating leukocytes and the cardiac fibroblasts, MMP-9 coordinates multiple aspects of LV remodeling. In this review, we will discuss recent research that has expanded our understanding of post-MI LV remodeling, including recent proteomic advances focused on the ECM compartment to provide novel functional and translational insights. This overview will summarize how our understanding of MMP-9 has evolved over the last decade and will provide insight into future directions that will drive our understanding of MMP-9-directed cardiac ECM turnover in the post-MI LV.