bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the evidence
Authors: Hudson Mark , Schuchmann Marcus
Published: November 2018

A consolidated overview of evidence for the effectiveness and safety/tolerability of hepatic encephalopathy (HE) treatment over the long term is currently lacking. We identified and assessed published evidence for the long-term (≥6 months) pharmacological management of HE with lactulose and/or rifaximin. A literature search was conducted in PubMed (cutoff date 05 March 2018) using the search terms ‘hepatic encephalopathy+rifaximin’ and ‘hepatic encephalopathy+lactulose’. All articles containing primary clinical data were manually assessed to identify studies in which long-term (≥6 months) effectiveness and/or safety/tolerability end points were reported for lactulose and/or rifaximin. Long-term effectiveness outcomes were reported in eight articles for treatment with lactulose alone and 19 articles for treatment with rifaximin, alone or in combination with lactulose. Long-term safety/tolerability outcomes were reported in six articles for treatment with lactulose alone and nine articles for treatment with rifaximin, alone or in combination with lactulose. These studies showed that lactulose is effective for the prevention of overt HE recurrence over the long term and that the addition of rifaximin to lactulose significantly reduces the risk of overt HE recurrence and HE-related hospitalization, compared with lactulose therapy alone, without compromising tolerability. Current evidence therefore supports recommendations for the use of lactulose therapy for the prevention of overt HE recurrence over the long term, and for the additional benefit of adding rifaximin to lactulose therapy. Addition of rifaximin to standard lactulose therapy may result in substantial reductions in healthcare resource utilization over the long term, by reducing overt HE recurrence and associated rehospitalization.
Nursing Interventions to Reduce Peripherally Inserted Central Catheter Occlusion for Cancer Patients
Authors: Pan Mengting , Meng Aifeng , Yin Rong , Zhi Xiaoxu , Du Shizheng , Shi Ruchu , Zhu Ping , Cheng Fang , Sun Mengqing , Li Cheng , Fang Hong
Published: November 2018

Background

Cancer patients are considered the most at risk of the consequences of catheter occlusion. Therefore, nursing interventions that can effectively reduce the occlusion of peripherally inserted central catheter (PICC) lines must be identified to ensure a smooth treatment.

Objective

This study aimed to evaluate nursing interventions to minimize PICC line occlusion and make recommended measures for preventing or decreasing occlusion and abnormal extubation.

Methods

Studies about PICC occlusion that were published up to January 2017 were searched and screened in PubMed, Web of Science, Science Direct (Elsevier), EMBASE, Cochrane Library, and Chinese databases CNKI and Wanfang. Two independent reviewers screened the literature in accordance with the inclusion and exclusion criteria, assessed the quality of the included studies, and extracted the data. Further meta-analysis was performed using RevMan 5.3.

Results

Thirteen trials were included. Meta-analysis revealed that education for nurses (relative risk, 0.31; 95% confidence interval, 0.19–0.51; P < .00001) was significantly associated with PICC occlusion, whereas PICC type (relative risk, 0.60; 95% confidence interval, 0.32–1.15; P = .12) was not significantly associated with PICC occlusion. The solution to washing pipes and the PICC insertion techniques were descriptively analyzed to reach statistical significance.

Conclusion

This study determined the correlation of PICC occlusion with the nurses’ knowledge and skills, PICC types, flushing liquid and methods, and insertion techniques.

Implications for Practice

The findings of this study can serve as a guide for clinical work and for developing targeted measures to reduce occlusion.
The Effect of Psychoeducation on Anxiety in Women Undergoing Their Initial Breast Cancer Screening Mammography
Authors: Lungulescu Cristian Virgil , Lungulescu Cristina , Lungulescu Livia Teodora , Artene Stefan-Alexandru , Cazacu Irina Mihaela , Varju Peter , Dinescu Sorin , Danciulescu Mihaela , Gheorman Victor
Published: November 2018

We conducted a prospective, randomized, single-blinded study to determine whether a psychoeducational intervention for patients undergoing screening mammography could influence the level of anxiety related to the procedure. Fifty women undergoing mammography for the first time were included in the study and randomized to two groups. In the study group, patients received a psychoeducational session before mammography. In the control group, psychoeducation was not applied. To evaluate the level of anxiety, we used the State-Trait Anxiety Inventory. State Anxiety Scale (S-Anxiety) score and Trait Anxiety Scale (T-Anxiety) scores were assessed before and after mammography in both groups. After evaluating the S-Anxiety score in the study group before mammography and after the procedure, a statistically significant difference (p = 0.043) was observed. In contrast, no statistically significant changes were noticed in the control group (p = 0.886). Our study showed that psychoeducation reduced state anxiety among the participants of a breast cancer screening.
Early Heart Rate Variability and Electroencephalographic Abnormalities in Acutely Brain-Injured Children Who Progress to Brain Death*
Authors: Piantino Juan A. , Lin Amber , Crowder Daniel , Williams Cydni N. , Perez-Alday Erick , Tereshchenko Larisa G. , Newgard Craig D.
Published: November 2018

Objectives:

Heart rate variability is controlled by the autonomic nervous system. After brain death, this autonomic control stops, and heart rate variability is significantly decreased. However, it is unknown if early changes in heart rate variability are predictive of progression to brain death. We hypothesized that in brain-injured children, lower heart rate variability is an early indicator of autonomic system failure, and it predicts progression to brain death. We additionally explored the association between heart rate variability and markers of brain dysfunction such as electroencephalogram and neurologic examination between brain-injured children who progressed to brain death and those who survived.

Design:

Retrospective case-control study.

Setting:

PICU, single institution.

Patients:

Children up to 18 years with a Glasgow Coma Scale score of less than 8 admitted between August of 2016 and December of 2017, who had electrocardiographic data available for heart rate variability analysis, were included. Exclusion criteria: patients who died of causes other than brain death. Twenty-three patients met inclusion criteria: six progressed to brain death (cases), and 17 survived (controls). Five-minute electrocardiogram segments were used to estimate heart rate variability in the time domain (sd of normal-normal intervals, root mean square successive differences), frequency domain (low frequency, high frequency, low frequency/high frequency ratio), Poincaré plots, and approximate entropy.

Interventions:

None.

Measurements and Main Results:

Patients who progressed to brain death exhibited significantly lower heart rate variability in the time domain, frequency domain, and Poincaré plots (p < 0.01). The odds of death increased with decreasing low frequency (odds ratio, 4.0; 95% CI, 1.2–13.6) and high frequency (odds ratio, 2.5; 95% CI, 1.2–5.4) heart rate variability power (p < 0.03). Heart rate variability was significantly lower in those with discontinuous or attenuated/featureless electroencephalogram versus those with slow/disorganized background (p < 0.03).

Conclusions:

These results support the concept of autonomic system failure as an early indicator of impending brain death in brain-injured children. Furthermore, decreased heart rate variability is associated with markers of CNS dysfunction such as electroencephalogram abnormalities.
Cardiac Arrest in the Pediatric Cardiac ICU: Is Medical Congenital Heart Disease a Predictor of Survival?*
Authors: Dhillon Gurpreet S. , Lasa Javier J. , Aggarwal Varun , Checchia Paul A. , Bavare Aarti C.
Published: November 2018

Objectives:

Children with medical cardiac disease experience poorer survival to hospital discharge after cardiopulmonary arrest compared with children with surgical cardiac disease. Limited literature exists describing epidemiology and factors associated with mortality in this heterogeneous population. We aim to evaluate the clinical characteristics and outcomes after cardiopulmonary arrest in medical cardiac patients.

Design:

We performed a retrospective review of pediatric cardiac patients who underwent cardiopulmonary resuscitation in a tertiary care cardiac ICU. Surgical cardiac patients underwent cardiac surgery immediately prior to ICU admission. Nonsurgical cardiac patients were divided into two groups based on the presence of congenital heart disease: congenital heart disease medical or noncongenital heart disease medical. Clinical and outcome variables were collected. Primary outcome was survival to hospital discharge.

Settings:

Texas Children’s Hospital cardiac ICU.

Patients:

Patients admitted to Texas Children’s Hospital cardiac ICU between January 2011 and December 2016.

Interventions:

None.

Measurements and Main Results:

Of 150 cardiopulmonary arrest events reviewed, 90 index events were included (46 surgical, 26 congenital heart disease medical, and 18 noncongenital heart disease medical). There was no difference in primary outcome among the three groups. The absence of an epinephrine infusion precardiopulmonary arrest was associated with increased odds of survival in the congenital heart disease medical group (p = 0.03). Noncongenital heart disease medical patients experienced pulseless ventricular tachycardia/ventricular fibrillation more frequently than congenital heart disease medical patients (p = 0.02). Congenital heart disease medical patients had trends toward longer cardiac arrest durations, higher prevalence of neurologic sequelae postcardiopulmonary arrest, and higher mortality when extracorporeal support at cardiopulmonary resuscitation was employed.

Conclusions:

Although trends in first documented rhythm, neurologic sequelae, and inotropic support prior to cardiopulmonary arrest were noted between groups, no significant differences in survival after cardiac arrest were seen. Larger scale studies are needed to better describe factors associated with cardiopulmonary arrest as well as survival in heterogeneous medical cardiac populations.
Hidden in plain sight: What remains to be discovered in the eukaryotic proteome?
Authors: Wood Valerie , Lock Antonia , Harris Midori A. , Rutherford Kim , Bähler Jürg , Oliver Stephen G.
Published: November 2018

The first decade of genome sequencing stimulated an explosion in the characterization of unknown proteins. More recently, the pace of functional discovery has slowed, leaving around 20% of the proteins even in well-studied model organisms without informative descriptions of their biological roles. Remarkably, many uncharacterized proteins are conserved from yeasts to human, suggesting that they contribute to fundamental biological processes. To fully understand biological systems in health and disease, we need to account for every part of the system. Unstudied proteins thus represent a collective blind spot that limits the progress of both basic and applied biosciences.

We use a simple yet powerful metric based on Gene Ontology (GO) biological process terms to define characterized and uncharacterized proteins for human, budding yeast, and fission yeast. We then identify a set of conserved but unstudied proteins in S. pombe, and classify them based on a combination of orthogonal attributes determined by large-scale experimental and comparative methods. Finally, we explore possible reasons why these proteins remain neglected, and propose courses of action to raise their profile and thereby reap the benefits of completing the catalog of proteins’ biological roles.
Deep Residual Learning for Neuroimaging: An application to Predict Progression to Alzheimer’s Disease
Authors: Abrol Anees , Bhattarai Manish , Fedorov Alex , Du Yuhui , Plis Sergey , Calhoun Vince D. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2018

This work investigates the suitability of deep residual neural networks (ResNets) for studying neuroimaging data in the specific application of predicting progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). We focus on predicting the subset of MCI individuals that would progress to AD within three years (progressive MCI) and the subset of MCI individuals that do not progress to AD within this period (stable MCI). This prediction was conducted first as a standard binary classification task by training a ResNet architecture using MCI individuals only, followed by a modified domain transfer learning version that additionally trained on the AD and cognitively normal (CN) individuals. For this modified inter-MCI classification task, the ResNet architecture achieved a significant performance improvement over the classical support vector machine and the stacked autoencoder machine learning frameworks (p< 0.005), numerically better than state-of-the-art performance in predicting progression to AD using structural MRI data alone (> 7% than the second-best performing method) and within 1% of the state-of-the-art performance considering learning using multiple structural modalities as well. The learnt predictive models in this modified classification task showed highly similar peak activations, significant correspondence of which in the medial temporal lobe and other areas could be established with previous reports in AD literature, thus further validating our findings. Our results highlight the possibility of early identification of modifiable risk factors for understanding progression to AD using similar advanced deep learning architectures.
Genomic signatures of evolutionary rescue in bats surviving white-nose syndrome
Authors: Gignoux-Wolfsohn Sarah A. , Pinsky Malin L. , Kerwin Kathleen , Herzog Carl , Hall MacKenzie , Bennett Alyssa B. , Fefferman Nina H. , Maslo Brooke
Published: November 2018

Rapid evolution of advantageous traits following abrupt environmental change can help populations grow and avoid extinction through evolutionary rescue. Here, we provide the first genetic evidence for rapid evolution in bat populations affected by white-nose syndrome (WNS). By comparing genetic samples from before and after little brown bat populations were decimated by WNS, we identified signatures of soft selection on standing genetic variation. This selection occurred at multiple loci in genes linked to hibernation behavior rather than immune function, suggesting that differences in hibernation strategy have allowed these bats to survive infection with WNS. Through these findings, we suggest that evolutionary rescue can be a conservationrelevant process even in slowly reproducing taxa threatened with extinction.
Macrophages utilize a bet-hedging strategy for antimicrobial activity in phagolysosomal acidification
Authors: Dragotakes Quigly , Stouffer Kaitlin , Fu Man Shun , Sella Yehonatan , Youn Christine , Yoon Insun , De Leon-Rodriguez Carlos M. , Freij Joudeh B. , Bergman Aviv , Casadevall Arturo
Published: November 2018

Microbial ingestion by a macrophage results in the formation of an acidic phagolysosome but the host cell has no information on the pH susceptibility of the ingested organism. This poses a problem for the macrophage and raises the fundamental question of how the phagocytic cell optimizes the acidification process to prevail. We analyzed the dynamical distribution of phagolysosomal pH in murine and human macrophages that had ingested live or dead Cryptococcus neoformans cells, or inert beads. Phagolysosomal acidification produced a range of pH values that approximated normal distributions, but these differed from normality depending on ingested particle type. Analysis of the increments of pH reduction revealed no forbidden ordinal patterns, implying that phagosomal acidification process was a stochastic dynamical system. Using simulation modeling, we determined that by stochastically acidifying a phagolysosome to a pH within the observed distribution, macrophages sacrificed a small amount of overall fitness to gain the benefit of reduced variation in fitness. Hence, chance in the final phagosomal pH introduces unpredictability to the outcome of the macrophage-microbe, which implies a bet-hedging strategy that benefits the macrophage. While bet hedging is common in biological systems at the organism level, our results show its use at the organelle and cellular level.
Discovery ofDrosophila melanogasterfrom Wild African Environments and Genomic Insights into Species History
Authors: Sprengelmeyer Quentin D. , Mansourian Suzan , Lange Jeremy D. , Matute Daniel R. , Cooper Brandon S. , Jirle Erling V. , Stensmyr Marcus C. , Pool John E.
Published: November 2018

A long-standing enigma concerns the geographic and ecological origins of the intensively studied vinegar fly,Drosophila melanogaster, a globally widespread species [1] which “has invariably appeared to be a strict human commensal” [2]. In spite of its sub-Saharan origins, this species has never been reported from undisturbed wilderness environments that might reflect its pre-commensal niche [3]. Here, we document the collection of 288D. melanogasterindividuals from African wilderness areas in Zambia, Zimbabwe, and Namibia. After sequencing the genomes of 17 flies collected from Kafue National Park, Zambia, we found reduced genetic diversity relative to town populations, elevated chromosomal inversion frequencies, and strong differences at specific genes including known insecticide targets. Combining these new genomes with prior data enabled us to gain novel insights into the history of this species’ geographic expansion. Our demographic estimates indicated that an expansion from southern Africa began approximately 10,000 years ago, with a Saharan crossing soon after, but expansion from the Middle East into Europe did not begin until roughly 1,400 years ago. This improved model of demographic history will provide a critical resource for future evolutionary and genomic studies of this key model organism. Our results add historical context to the species’ human association, and the opportunity to study wilderness populations opens the door for future studies on the biological basis of its adaptation to human environments.
Augmenting cognitive load during split-belt walking increases the generalization of motor memories across walking contexts
Authors: Mariscal Dulce M. , Iturralde Pablo A. , Torres-Oviedo Gelsy
Published: November 2018

Cognitive load plays a role on the movement recalibration induced by sensorimotor adaptation, but little is known about its impact on the generalization of movements from trained to untrained situations. We hypothesized that altering cognitive load by distracting subjects during sensorimotor adaptation would facilitate the generalization of recalibrated movements beyond the training condition. We reasoned that awareness of the novel condition inducing adaptation could be used to consciously contextualize movements to that particular situation. To test this hypothesis, young adults adapted their gait on a split-belt treadmill (moving their legs at different speeds) while they observed visual information that either distracted them or made them aware of the speed difference between their feet. We assessed the adaptation and aftereffects of spatial and temporal gait features known to adapt and generalize differently when walking on the treadmill or overground. We found similar adaptation and aftereffects on the treadmill across all groups. In contrast, both groups with altered cognitive load (i.e., distraction and awareness groups) generalized their movements from the treadmill to overground more than controls, who walked without altered cognitive load. Of note, this effect was only observed in temporal gait features, which are less susceptible to online motor adjustments, and were eliminated upon experiencing large errors by briefly removing the split perturbation during adaptation (i.e., catch trial). Taken together, increasing cognitive demands during sensorimotor adaptation facilitates the generalization of movement recalibration, but this cognitive-mediated effect cannot eliminate the specificity of actions due to context-specific errors.

New and Noteworthy

Little is known about how cognition affects the generalization of motor recalibration induced by sensorimotor adaptation paradigms. We showed that augmenting cognitive load during adaptation on a split-belt treadmill led to greater recalibration of movements without the training device. However, this effect was eliminated when unusual motor errors were experienced on the treadmill. Thus, cognition can influence the generalization of sensorimotor adaptation, but it cannot suppress the context-specificity originated by the errors that one feels.
Single Agent and Synergistic Activity of Maritoclax with ABT-263 in Nasopharyngeal Carcinoma (NPC) Cell Lines
Authors: Xiang Lian Benedict Shi , Lo Kwok-Wai , Soo-Beng Khoo Alan , Mohana-Kumaran Nethia
Published: November 2018

Objective

The BCL-2 anti-apoptotic proteins are over-expressed in many cancers and hence are attractive therapeutic targets. In this study we tested the sensitivity of two NPC cell lines HK1 and C6661-1 to Maritoclax which is reported to repress anti-apoptotic protein MCL-1 and BH3 mimetic ABT-263 which selectively inhibits anti-apoptotic proteins BCL-2, BCL-XL and BCL-w. We investigated the sensitization of the NPC cell lines to these drugs using the SYBR Green I assay and 3D NPC spheroids.

Results

We report that Maritoclax repressed MCL-1, BCL-2, and BCL-XL in a dose- and time-dependent manner and displayed a single agent activity in inhibiting cell proliferation of the NPC cell lines. Moreover, combination of Maritoclax and ABT-263 exhibited synergistic cell proliferation effect in the HK1 cell line. Similar results were obtained in the 3D spheroids. More notably, 3D spheroids either treated with single agent Maritoclax or combination with ABT-263 over 10 days did not develop resistance to the treatment rapidly. Collectively, the findings illustrate that Maritoclax as a single agent or combination with BH3 mimetics could be a potential treatment strategy for NPC but further studies in preclinical models are warranted to fully unravel the prospects of these drugs.
The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
Authors: Echeverria Pablo C. , Bhattacharya Kaushik , Joshi Abhinav , Wang Tai , Picard Didier
Published: November 2018

The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.
Detoxification of host plant phenolic aglycones by the spruce budworm
Authors: Donkor Dominic , Mirzahosseini Zahra , Bede Jacquie , Bauce Eric , Despland Emma
Published: November 2018

This study examines the post-ingestive fate of two host-plant derived small-molecule phenolics (the acetophenones piceol and pungenol) that have previously been shown to be toxic to the outbreaking forest pest, spruce budworm (Choristoneura fumiferana). We test first whether these compounds are transformed during passage through the midgut, and second whether the budworm upregulates activity of the detoxification enzyme glutathione-s-transferase (GST) in response to feeding on these compounds. Insects were reared on either foliage or artificial diet to the fourth instar, when they were transferred individually to one of two treatment diets, either control or phenolic-laced, for approximately 10 days, after which midguts were dissected out and used for Bradford soluble protein and GST enzyme activity analysis. Frass was collected and subjected to HPLC-DAD-MS. HPLC showed that the acetophenones do not autoxidize under midgut pH conditions, but that glucose- and glutathione-conjugates are present in the frass of insects fed the phenolic-laced diet. GST enzyme activity increases in insects fed the phenolic-laced diet, in both neutral pH and alkaline assays. These data show that the spruce budwom exhibits counter-adaptations to plant phenolics similar to those seen in angiosperm feeders, upregulating an important detoxifying enzyme (GST) and partially conjugating these acetophenones prior to elimination, but that these counter-measures are not totally effective at mitigating toxic effects of the ingested compounds in the context of our artifical-diet based laboratory experiment.
5’ UTR recruitment of eIF4GI or DAP5 drives cap-independent translation for a subset of human mRNAs
Authors: Haizel Solomon A. , Bhardwaj Usha , Gonzalez Ruben L. , Mitra Somdeb , Goss Dixie J.
Published: November 2018

During unfavorable human cellular conditions (e.g., tumor hypoxia, viral infection, etc.), canonical, cap-dependent mRNA translation is suppressed. Nonetheless, a subset of physiologically important mRNAs (e.g., HIF-1α, FGF-9, and p53) is still translated by an unknown, cap-independent mechanism. Additionally, expression levels of eIF4G and its homolog, death associated protein 5 (DAP5), are elevated. Using fluorescence anisotropy binding studies, luciferase reporter-based in vitro translation assays, and mutational analyses, here we demonstrate that eIF4GI and DAP5 specifically bind to the 5’ UTRs of these cap-independently translated mRNAs. Surprisingly, we find that the eIF4E binding domain of eIF4GI increases not only the binding affinity, but also the selectivity among these mRNAs. We further demonstrate that the affinities of eIF4GI and DAP5 binding to these 5’ UTRs correlate with the efficiency with which these factors drive cap-independent translation of these mRNAs. Integrating the results of our binding and translation assays, we show that eIF4GI and/or DAP5 are critical for recruitment of a specific subset of mRNAs to the ribosome and provide mechanistic insight into their cap-independent translation.
Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection
Authors: Ye Chun Jimmie , Chen Jenny , Villani Alexandra-Chloé , Gate Rachel E. , Subramaniam Meena , Bhangale Tushar , Lee Mark N. , Raj Towfique , Raychowdhury Raktima , Li Weibo , Rogel Noga , Simmons Sean , Imboywa Selina H. , Chipendo Portia I. , McCabe Cristin , Lee Michelle H. , Frohlich Irene Y. , Stranger Barbara E. , De Jager Philip L. , Regev Aviv , Behrens Tim , Hacohen Nir
Published: November 2018

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.
Crystal packing and theoretical analysis of halogen- and hydrogen-bonded hydrazones from pharmaceuticals. Evidence of type I and II halogen bonds in extended chains of dichloromethane
Authors: Berger Gilles , Soubhye Jalal , Wintjens René , Robeyns Koen , Meyer Franck
Published: November 2018

The supramolecular assembly of halogenated and hydroxyl hydrazones derived from two well known pharmaceuticals, isoniazid (IsX, where X = I, Br, OH) and hydralazine (HyX, where X = I, Br, OH), was studied by X-ray crystallography and theoretical methods. Crystal packing of IsI and HyI shows weak I...N and I...π halogen bonds, whereas the hydrogen bonds are dominant in the brominated scaffolds IsBr and HyBr. Although the calculated I...N interaction strength appears almost three times weaker than the O—H...N contacts in the isoniazid-based hydrazones, the higher directionality of the halogen bonds induces a linear and planar architecture of self-complementary tectons, observed only with the help of a bridging water molecule in the case of IsOH. Finally, the X-ray structure of HyOH is characterized by an unexpected linear arrangement of clathrated dichloromethane molecules bound through type I and II halogen bonds. This rare phenomenon, observed in less than ten structures, was studied by coupled cluster-based energy decomposition.
Best practice example of CSR and S&E engagement in emerging economies: analysis of a case study based in China
Authors: Fornes Gaston , Lopez Belen , Bierens de Haan Melanie , Blanch Javier
Published: November 2018

Purpose

The paper analyses social and environmental engagement, stakeholders’ relations and corporate social responsibility (CSR) strategies/options along with their underlying mechanisms of firms operating in China.

Design/methodology/approach

It does this through the analysis of a unique case study using data collected from internal members and external stakeholders of the company framed within stakeholder theory.

Findings

Within the Aguinis and Glavas (2012) framework, the results show that the company’s resources and values can act as a mediator, their high visibility and scale can act as a moderator, and their self-regulation can act as a predictor in weak institutional contexts. Also, the findings show that employees’ perceptions of visionary leadership can act as a mediator, and that the alignment in the vision/values/beliefs of the chief executive officer with those of the shareholders can act as moderators.

Originality/value

The paper intends to contribute to the literature on CSR in China by analysing a specific type of investor, the socially responsible investor, neglected in the CSR literature, and by studying multilevel (individual/organisational/institutional) social and environmental engagement, stakeholders’ relations and CSR strategies/options in an evolving institutional environment.
A second KRT71 allele in curly coated dogs
Authors: Bauer A. , Hadji Rasouliha S. , Brunner M. T. , Jagannathan V. , Bucher I. , Bannoehr J. , Varjonen K. , Bond R. , Bergvall K. , Welle M. M. , Roosje P. , Leeb T.
Published: November 2018

Major characteristics of coat variation in dogs can be explained by variants in only a few genes. Until now, only one missense variant in the KRT71 gene, p.Arg151Trp, has been reported to cause curly hair in dogs. However, this variant does not explain the curly coat in all breeds as the mutant 151Trp allele, for example, is absent in Curly Coated Retrievers. We sequenced the genome of a Curly Coated Retriever at 22× coverage and searched for variants in the KRT71 gene. Only one protein‐changing variant was present in a homozygous state in the Curly Coated Retriever and absent or present in a heterozygous state in 221 control dogs from different dog breeds. This variant, NM_001197029.1:c.1266_1273delinsACA, was an indel variant in exon 7 that caused a frameshift and an altered and probably extended C‐terminus of the KRT71 protein NP_001183958.1:p.(Ser422ArgfsTer?). Using Sanger sequencing, we found that the variant was fixed in a cohort of 125 Curly Coated Retrievers and segregating in five of 14 additionally tested breeds with a curly or wavy coat. KRT71 variants cause curly hair in humans, mice, rats, cats and dogs. Specific KRT71 variants were further shown to cause alopecia. Based on this knowledge from other species and the predicted molecular consequence of the newly identified canine KRT71 variant, it is a compelling candidate causing a second curly hair allele in dogs. It might cause a slightly different coat phenotype than the previously published p.Arg151Trp variant and could potentially be associated with follicular dysplasia in dogs.
Ticagrelor does not impact patient‐reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study
Authors: Kanter Julie , Abboud Miguel R. , Kaya Banu , Nduba Videlis , Amilon Carl , Gottfridsson Christer , Rensfeldt Martin , Leonsson‐Zachrisson Maria ,   the HESTIA2 study investigators
Published: November 2018

Ticagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso‐occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18–30 years) 1:1:1 to twice‐daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient‐reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non‐major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary‐reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study.
Pharmacological modulation of mitochondrial ion channels
Authors: Leanza Luigi , Checchetto Vanessa , Biasutto Lucia , Rossa Andrea , Costa Roberto , Bachmann Magdalena , Zoratti Mario , Szabo Ildiko
Published: November 2018

The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria‐specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear‐cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage‐dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane‐located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large‐scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer.

Linked Articles

This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc
Character: A Developmental System
Authors: Nucci Larry
Published: November 2018

In this article, I discuss character as a system that includes four components: moral cognition, other‐related social–emotional capacities and skills, self‐regarding capacities for executive control and self‐regulation, and discourse skills for responsive engagement and an orientation for principled moral change. The character system is active, adjusting itself in response to social and emotional experiences and in an effort to keep the components of the system working harmoniously. It is dynamically related to the context, generating decisions and actions that are coherent within but not entirely consistent across contexts. Decisions and actions alter the self‐system, thereby affecting subsequent decisions and actions. The character system is located within a larger self‐system, and it interacts with that self‐system in a relationship that is also self‐maintaining. This two‐way interaction alters both the character system and the self‐system, leading to growth in character and related changes in personal identity and the sense of self. This system view contrasts with traditional definitions of character in terms of virtues.
High prevalence of toothache among Great East Japan Earthquake survivors living in temporary housing
Authors: Tsuchiya Masahiro , Aida Jun , Watanabe Takashi , Shinoda Masamichi , Sugawara Yumi , Tomata Yasutake , Yabe Yutaka , Sekiguchi Takuya , Watanabe Makoto , Osaka Ken , Sasaki Keiichi , Hagiwara Yoshihiro , Tsuji Ichiro
Published: November 2018

Objectives

The Great East Japan Earthquake and subsequent tsunami cause large‐scale destruction in the north‐eastern coastal areas in Japan, and forced many survivors to relocate to prefabricated temporary housing, a typical emergency accommodation. Based on the hypothesis that higher toothache prevalence among the disaster survivors is associated with postdisaster distress, we determined the impact of temporary residential environment as potential stressor on the subjective toothache prevalence.

Methods

A repeated cross‐sectional health survey based on self‐reported questionnaire was conducted in 2776 disaster survivors, of whom 1446 participants underwent dental examination by dentists. Housing type was categorized into three groups including the same housing as before the earthquake, temporary housing and rented/new housing. The association of housing type with subjective toothache prevalence was examined using multivariate logistic regression analysis in all subjects and subgroup analysis in dental examination applicants. Stratified analysis by survey wave was applied with inclusion of covariates such as the socio‐demographic factors, and presence of insomnia and psychological distress. In subgroup analysis, presence of dental caries and gum problems in dental examination were included as factors of direct exposure to subjective toothache.

Results

In the first survey wave, the participants living in the temporary housing had significantly higher odds ratio (OR) for toothache prevalence compared to the participants living in the same housing (OR: 3.76, 95% confidence interval [CI]: 1.85‐7.65, P < 0.001); whereas in all other survey waves, there was no significant difference. Subgroup analysis of dental examination applicants confirmed the presence of significant association of subjective toothache prevalence in the temporary housing group alone (OR: 3.27, 95% CI: 1.38‐7.76, P = 0.004), but not in the rented/new housing group (OR: 1.50, 95% CI: 0.57‐3.91, P = 0.411), even after adjusting for covariates related to oral findings.

Conclusion

Temporary housing may be a factor to increase the risk of subjective toothache among disaster survivors only at postdisaster acute phase.
The Movements of Working Children and the International Labour Organization. A Lesson on Enforced Silence
Authors: Liebel Manfred , Invernizzi Antonella
Published: November 2018

Relations between the International Labour Organization (ILO) and grassroots movements of working children are characterised by tensions. Working children's claim to participate in conceptualising child labour policy is increasingly rejected. Most recently, in November 2017, the Latin American Movement of Working Children and Adolescents (MOLACNATs) lodged a complaint with the UN Committee on the Rights of the Child over violations of rights enshrined in the 1989 UN Convention on the Rights of the Child. This article reconstructs the history of working children's movements and their communication with ILO since the 1990s.
Priming the Pump: Public Investment, Private Mortgage Investment, and Violent Crime
Authors: Shrider Emily A. , Ramey David M.
Published: November 2018

Recent neighborhood crime research suggests that increased mortgage investment in local communities can help reduce street crime by defending against physical decline and improving perceptions of the neighborhood, which make informal social control more likely. Unfortunately, the neighborhoods that could benefit the most from this relationship are the least likely to get private mortgage investment, as mortgages tend to flow towards neighborhoods that are already stable. In this paper, we examine whether public investment, which can be targeted at disadvantaged neighborhoods, can play a similar role as private investment in influencing neighborhood outcomes. Specifically, we examine whether Seattle's Neighborhood Matching Fund program, a municipal initiative that provides matching funds to local organizations planning neighborhood improvement projects, is associated with reductions in crime, both directly, through community–building and physical improvements, and indirectly, by encouraging increased private mortgage investment.
A doxycycline‐treated hydroxyapatite implant surface attenuates the progression of peri‐implantitis: A radiographic and histological study in mice
Authors: Ding Lin , Zhang Peng , Wang Xin , Kasugai Shohei
Published: November 2018

Background

Oral rehabilitation with dental implants has become increasingly common; however, the increase of peri‐implantitis is a great concern. Doxycycline (DOX) is a widely used antibiotic that inhibits bacteria growth, inflammation, and bone resorption.

Objectives

To evaluate the progression of peri‐implantitis of hydroxyapatite (HA)‐coated implants with (5 mg/mL, DOX group) or without (HA group) DOX treatment on the surface.

Materials and Methods

The maxillary first molars of 20 male mice were extracted. Eight weeks later, small titanium screw implants coated with thin HA and treated with or without DOX were placed at the extracted sites. Four weeks after implant placement, half of the animals in both groups were sacrificed, and ligatures were placed around the implant necks in the other half. These mice were sacrificed 4 weeks later. The bone around the implants was examined radiologically and histologically.

Results

Four weeks after the ligature placement, the radiographic measurements revealed that peri‐implant bone levels of palatal and mesial sites, and histological measurements showed that bone levels of mesial and distal sites in the DOX group were significantly higher than those in the HA group.

Conclusions

The present results indicating that the DOX‐treated HA implant surface attenuates the progression of peri‐implantitis.
IL‐2mAb reduces demyelination after focal cerebral ischemia by suppressing CD8+ T cells
Authors: Zhou Yu‐Xi , Wang Xin , Tang Dan , Li Yan , Jiao Ying‐Fu , Gan Yu , Hu Xiao‐Ming , Yang Li‐Qun , Yu Wei‐Feng , Stetler Ruth Anne , Li Pei‐Ying , Wen Da‐Xiang
Published: November 2018

Aims

Demyelination, one of the major pathological changes of white matter injury, is closely related to T‐cell–mediated immune responses. Thus, we investigate the role of an IL‐2 monoclonal antibody (IL‐2mAb, JES6‐1) in combatting demyelination during the late phase of stroke.

Methods

IL‐2mAb or IgG isotype antibody (0.25 mg/kg) was injected intraperitoneally 2 and 48 hours after middle cerebral artery occlusion (MCAO) surgery. Infarct volume, peripheral immune cell infiltration, microglia activation, and myelin loss were measured by 2,3,5‐triphenyte trazoliumchloride staining, immunofluorescence staining, flow cytometry, and Western blot. Intraperitoneal CD8 neutralizing antibody (15 mg/kg) was injected 1 day before MCAO surgery to determine the role of CD8+ T cells on demyelinating lesions.

Results

IL‐2mAb treatment reduced brain infarct volume, attenuated demyelination, and improved long‐term sensorimotor functions up to 28 days after dMCAO. Brain infiltration of CD8+ T cells and peripheral activation of CD8+ T cells were both attenuated in IL‐2 mAb‐treated mice. The protection of IL‐2mAb on demyelination was abolished in mice depleted of CD8+ T cell 1 week after stroke.

Conclusions

IL‐2mAb preserved white matter integrity and improved long‐term sensorimotor functions following cerebral ischemic injury. The activation and brain infiltration of CD8+ T cells are detrimental for demyelination after stroke and may be the major target of IL‐2mAb posttreatment in the protection of white matter integrity after stroke.