bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide Association study of facial morphology identifies novel genetic loci in Han Chinese
Authors: Huang Yin , Li Dan , Qiao Lu , Liu Yu , Peng Qianqian , Wu Sijie , Zhang Manfei , Yang Yajun , Tan Jingze , Xu Shuhua , Jin Li , Wang Sijia , Tang Kun , Grünewald Stefan
Published: July 2019

Human face is a heritable surface with many complex sensory organs. In recent years, many genetic loci associated with facial features have been reported in different populations, yet there is a lack for the Han Chinese population. We report a genome-wide association analysis of 3D normal human faces in 2659 Han Chinese with two groups of phenotypes, the partial and whole face phenotypes and the distance and angle phenotypes. We found significant signals in five genomic regions with traits related to nose or eyes, including rs970797 in 2q31.1 near HOXD1 and MTX2, rs16897517 in 8q22.2 at intron of VPS13B, rs9995821 in 4q31.3 near DCHS2 and SFRP2, rs12636297 in 3q23 near PISRT1, and rs12948076 in 17q24.3 near SOX9 and CASC17. We visualized changes in facial morphology by comparing the volume of local areas and observed that these nose-related loci were associated with different features of the nose, including nose prominence, nasion height, and nostril shape, suggesting that the nose underlies precise genetic regulation. These results provide a more comprehensive understanding of the relationship between genetic loci and human facial morphology.

Author Summary

Human face as a combination of delicate sensory organs has a strong genetic component, as evidenced by the identical appearance in twins and shared facial features in close relatives. Although facial genetics have been studied in different populations, our knowledge between genetic markers with facial features is still limited. In this paper, we found genetic variants associated with nose and eyes through a large-scale high-resolution 3D facial genetic study on the Han Chinese population. We observed that these nose-related loci were associated with different features of the nose, including nose prominence, nasion height, and nostril shape, which suggests the nose underlies precise genetic regulation. Intriguingly, we noted that genes (DCHS2 and SFRP2) related to one of these loci are differentially expressed in human and chimp cranial neural crest cells, which plays a crucial role in the early formation of facial morphology. The ongoing genetic studies of facial morphology will improve our understanding of human craniofacial development, and provide potential evolution evidence of human facial features.
Identifying maintenance hosts and risk factors for infection with Dichelobacter nodosus in free-ranging wild ruminants in Switzerland: a prevalence study
Authors: Moore-Jones Gaia , Ardüser Flurin , Dürr Salome , Brawand Stefanie Gobeli , Steiner Adrian , Zanolari Patrik , Ryser-Degiorgis Marie-Pierre
Published: July 2019

Footrot is a worldwide economically important, painful, contagious bacterial hoof disease of domestic and wild ungulates caused by Dichelobacter nodosus (D. nodosus). Benign and virulent strains have been identified in sheep presenting mild and severe lesions, respectively. However, in Alpine ibex (Capra ibex) both strains have been associated with severe, fatal lesions. In Switzerland a nationwide footrot control program for sheep focusing on the virulent strain shall soon be implemented. The aim of this cross-sectional study was to estimate the nationwide prevalence of both strains of D. nodosus in four wild indigenous ruminant species and to identify potential susceptible maintenance hosts that could be a reinfection source for sheep. During two years (2017-2018), interdigital swabs of 1,821 wild indigenous ruminants species (Alpine ibex; Alpine chamois, Rupicapra rupicapra; roe deer, Capreolus capreolus; red deer, Cervus elaphus) were analysed by Real-Time PCR. Furthermore, observed interspecies interactions were documented for each sample. Overall, we report a low prevalence of D. nodosus in all four indigenous wild ruminants, for both the benign (1.97%, N = 36, of which 31 red deer) and virulent (0.05%, N = 1) strain of D. nodosus. Footrot lesions were documented in one ibex with the virulent strain, and in one ibex with the benign strain. Interactions with domestic livestock occurred mainly with cattle and sheep. In conclusion, the data suggest that domestic ungulates represent a significant source of infection for wild ungulates, while wild ruminants are likely irrelevant for the maintenance and spread of D. nodosus. Furthermore, we add evidence that both D. nodosus strains can be associated with severe disease in Alpine ibex. These data are crucial for the upcoming nationwide control program and reveal that wild ruminants should not be considered as a threat to footrot control in sheep in this context.
Resistome metagenomics from plate to farm: the resistome and microbial composition during food waste feeding and composting on a Vermont poultry farm
Authors: Eckstrom Korin , Barlow John W.
Published: July 2019

Food waste diversion and composting, either mandated or voluntary, are growing alternatives to traditional waste disposal. An acceptable source of agricultural feed and composting material, methane-emitting food residuals, including post-consumer food scraps, are diverted from landfills allowing recapture of nutrients that would otherwise be lost. However, risk associated with the transfer of antimicrobial resistant bacteria (ARB), antibiotic resistance genes (ARGs), or pathogens from food waste is not well characterized. Using shotgun metagenomic sequencing, ARGs, microbial content, and associated virulence factors were successfully identified across samples from an integrated poultry farm that feeds post-consumer food waste. A total of 495 distinct bacterial species or sub-species, 50 ARGs, and 54 virulence gene sequences were found. ARG sequences related to aminoglycoside, tetracycline, and macrolide resistance were most prominent, while most virulence gene sequences were related to transposon or integron activity. Microbiome content was distinct between on-farm samples and off-farm food waste collection sites, with a reduction in pathogens throughout the composting process. While most samples contained some level of resistance, only 3 resistance gene sequences occurred in both on- and off-farm samples and no multidrug resistance (MDR) gene sequences persisted once on the farm. The risk of incorporating novel or multi-drug resistance from human sources appears to be minimal and the practice of utilizing post-consumer food scraps as feed for poultry and composting material may not present a significant risk for human or animal health. Pearson correlation and co-inertia analysis identified a significant interaction between resistance and virulence genes (P = 0.05, RV = 0.67), indicating that ability to undergo gene transfer may be a better marker for ARG risk than presence of specific bacterial species. This work expands the knowledge of ARG fate during food scrap animal feeding and composting and provides a methodology for reproducible analysis.
MEArec: a fast and customizable testbench simulator for ground-truth extracellular spiking activity
Authors: Buccino Alessio P. , Einevoll Gaute T.
Published: July 2019

When recording neural activity from extracellular electrodes, bothin vivoandin vitro, spike sorting is a required and very important processing step that allows for identification of single neurons’ activity. Spike sorting is a complex algorithmic procedure, and in recent years many groups have attempted to tackle this problem, resulting in numerous methods and software packages. However, validation of spike sorting techniques is complicated. It is an inherently unsupervised problem and it is hard to find universal metrics to evaluate performance. Simultaneous recordings that combine extracellular and patch-clamp or juxtacellular techniques can provide ground-truth data to evaluate spike sorting methods. However, their utility is limited by the fact that only a few cells can be measured at the same time. Simulated ground-truth recordings can provide a powerful alternative mean to rank the performance of spike sorters. We present hereMEArec, a Python-based software which permits flexible and fast simulation of extracellular recordings.MEArecallows users to generate extracellular signals on various customizable electrode designs and can replicate various problematic aspects for spike sorting, such as bursting, spatio-temporal overlapping events, and drifts. We expectMEArecwill provide a common testbench for spike sorting development and evaluation, in which spike sorting developers can rapidly generate and evaluate the performance of their algorithms.
The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders
Authors: Gerrard Dave T. , Berry Andrew A. , Jennings Rachel E. , Birket Matthew J , Withey Sarah J , Short Patrick , Jiménez-Gancedo Sandra , Firbas Panos N , Donaldson Ian , Sharrocks Andrew D. , Hanley Karen Piper , Hurles Matthew E , Gomez-Skarmeta José Luis , Bobola Nicoletta , Hanley Neil A.
Published: July 2019

How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of in vitro stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we studied histone modifications across thirteen tissues during human organogenesis. We integrated the data with transcription to build the first overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partitioned into discrete states without showing bivalency. Key developmental gene sets were actively repressed outside of the appropriate organ. Candidate enhancers, functional in zebrafish, allowed imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allowed correlation to unanticipated target genes. Taken together, the data provide a new, comprehensive genomic framework for investigating normal and abnormal human development.
Neoteny in visual system development of the spotted unicornfish,Naso brevirostris(Acanthuridae)
Authors: Tettamanti Valerio , de Busserolles Fanny , Lecchini David , Marshall Justin , Cortesi Fabio
Published: July 2019

Ontogenetic changes of the visual system are often correlated to shifts in habitat and feeding behaviour of animals. Coral reef fishes begin their lives in the pelagic zone and then migrate to the reef. This transition of habitat frequently involves a change in diet and light environment as well as major morphological modifications. The spotted unicornfish,Naso brevirostris, is known to shift diet from zooplankton to algae and back to zooplankton when transitioning from larval to juvenile and then to adult stages. Concurrently,N. brevirostrisalso moves from an open pelagic to a coral-associated habitat before migrating up in the water column when reaching adulthood. Using retinal mapping techniques, we discovered that the distribution and density of ganglion and photoreceptor cells inN. brevirostrisdo not change with the habitat or the feeding habits of each developmental stage. Instead, fishes showed a neotenic development with a slight change from larval to juvenile stages and not many modifications thereafter. Visual gene expression based on RNA sequencing mirrored this pattern; independent of stage, fishes mainly expressed three cone opsin genes (SWS2B, RH2B, RH2A), with a quantitative difference in the expression of the green opsin genes (RH2AandRH2B) when transitioning from larvae to juveniles. Hence, contrary to the ontogenetic changes found in many animals, the visual system is fixed early on inN. brevirostrisdevelopment calling for a thorough analysis of visual system development of the reef fish community.
Neural correlates of experience with CCTV surveillance of naturalistic prosocial and antisocial interactions: a reverse correlation analysis
Authors: Gillard Julia A. , Petrini Karin , Noble Katie , Rodriguez Perez Jesus A. , Pollick Frank E.
Published: July 2019

Previous research using reverse correlation to explore the relationship between brain activity and presented image information found that Face Fusiform Area (FFA) activity could be related to the appearance of faces during free viewing of the Hollywood movie “The Good, the Bad, and the Ugly” (Hasson, et al, 2004). We applied this approach to the naturalistic viewing of unedited footage of city-centre closed-circuit television (CCTV) surveillance. Two 300 second videos were used, one containing prosocial activities and the other antisocial activities. Brain activity revealed through fMRI as well as eye movements were recorded while fifteen expert CCTV operators with a minimum of 6 months experience of CCTV surveillance alongside an age and gender matched control group of fifteen novice viewers were scanned while watching the videos. Independent scans functionally localized FFA and posterior Superior Temporal Sulcus (pSTS) activity using faces/houses and intact/scrambled point-light biological motion displays respectively. Reverse correlation revealed peaks in FFA and pSTS brain activity corresponding to the expert and novice eye movements directed towards faces and biological motion across both videos. In contrast, troughs in activation corresponded to camera-induced motion when a clear view of visual targets were temporarily not available. Our findings, validated by the eye movement data, indicate that the predicted modulation of brain activity occurs as a result of salient features of faces and biological motion embedded within the naturalistic stimuli. The examination of expertise revealed that in both pSTS and FFA the novices had significantly more activated timeframes than the experienced observers for the prosocial video. However, no difference was found for the antisocial video. The modulation of brain activity, as well as the effect of expertise gives a novel insight into the underlying visual processes in an applied real-life task.
Budgeting and portfolio allocation for biosecurity measures
Authors: Kompas Tom , Chu Long , Van Ha Pham , Spring Daniel
Published: July 2019

This paper presents a practical model for optimally allocating a budget across different biosecurity threats and measures (e.g. prevention or border quarantine, active surveillance for early detection, and containment and eradication measures) to ensure the highest rate of return. Our portfolio model differs from the common principle, which ranks alternative projects by their benefit cost ratios and picks the one that generates the highest average benefit cost ratio. The model we propose, instead, aims to allocate shares of the budget to the species where it is most cost‐effective, and consequently determine the optimal scale of the control program for each threat under varying budget constraints. The cost‐effectiveness of each block of budget spent on a threat is determined by minimising its expected total cost, including the damages it inflicts, and the control expenditures incurred in preventing or mitigating damages. As an illustration, the model is applied to the optimal allocation of a budget across four of Australia's most dangerous pests and diseases: red imported fire ants; foot‐and‐mouth disease; papaya fruit fly; and orange hawkweed. The model can readily be extended to consider more species and activities, and more complex settings including cases where detailed spatial and temporal information needs to be considered.
Auditors’ Quantitative Materiality Judgments: Properties and Implications for Financial Reporting Reliability
Authors: CHOUDHARY PREETI , MERKLEY KENNETH , SCHIPPER KATHERINE
Published: July 2019

We analyze data made available through the PCAOB (Public Company Accounting Oversight Board) to provide descriptive evidence on the properties of auditors’ actual quantitative materiality judgments and the implications of those judgments for financial reporting. Auditors’ quantitative materiality judgments do not appear to result simply from applying conventional rules of thumb (e.g., 5% of pretax income), but instead are associated with size‐related financial statement outcomes (income, revenues, and assets), where the relative importance of the size‐related outcomes varies with client characteristics such as financial performance. Using the distribution of actual materiality amounts reported by auditors to the PCAOB as part of the audit‐inspection process, we construct a materiality‐judgment measure that locates a specific materiality amount within a normal range that is both comparable across varying client characteristics and supported by guidance in audit firm internal policy manuals. We find that looser materiality (an amount closer to the high end of a normal materiality range) is associated with fewer audit hours and lower audit fees, supporting the construct validity of this measure. We also find that looser materiality is associated with lower amounts of proposed audit adjustments and, in extreme cases, with a greater incidence of restatements, highlighting the importance of auditor materiality assessments for financial reporting reliability.
Staff perceptions of the emergency department working environment: An international cross‐sectional survey
Authors: Crilly Julia , Greenslade Jaimi H , Johnston Amy , Carlström Eric , Thom Ogilvie , Abraham Louisa , Mills Donna , Wallis Marianne
Published: July 2019

Objectives

The aims of this study were to describe clinical staff perceptions of their ED working environment and to explore associations between staff demographics, coping styles and the work environment.

Methods

A cross‐sectional study was conducted in one Swedish ED and two Australian EDs in 2015–2016. Descriptive statistics were used to explore stressors, coping styles and aspects of the working environment for the combined cohort and the cohort split by age, sex, professional role, years of employment in the ED and country. Regression analyses examined the impact of coping style and demographic characteristics on staff perceptions of the working environment.

Results

Two hundred and six ED staff completed the survey (response rate: 64%). Factors most stressful for ED staff included death or sexual abuse of a child, heavy workload and poor skill mix. Staff perceptions of the working environment differed based on age, sex, country, tenure and job role. Regression analysis of perceptions of the work environment on demographics and coping strategies revealed that negative coping strategies were associated with low self‐realisation, high workload, high conflict and high nervousness. Active coping and positive thinking were associated with increased self‐realisation. Positive thinking was associated with lower levels of conflict.

Conclusions

Employees engaging in positive coping strategies had more positive perceptions of the work environment, while those engaging in maladaptive coping strategies reported negative perceptions of the work environment. These data suggest that strategies that promote the use of active coping and positive thinking should be encouraged and warrant further research in the ED.
Patterns of host cell inheritance in the bacterial symbiosis of whiteflies
Authors: Xu Xiao‐Rui , Li Na‐Na , Bao Xi‐Yu , Douglas Angela E. , Luan Jun‐Bo
Published: July 2019

Whiteflies possess bacterial symbionts Candidatus Portiera aleyrodidium that are housed in specialized cells called bacteriocytes and are faithfully transmitted via the ovary to insect offspring. In one whitefly species studied previously, Bemisia tabaci MEAM1, transmission is mediated by somatic inheritance of bacteriocytes, with a single bacteriocyte transferred to each oocyte and persisting through embryogenesis to the next generation. Here, we investigate the mode of bacteriocyte transmission in two whitefly species, B. tabaci MED, the sister species of MEAM1, and the phylogenetically distant species Trialeurodes vaporariorum. Microsatellite analysis supported by microscopical studies demonstrates that B. tabaci MED bacteriocytes are genetically different from other somatic cells and persist through embryogenesis, as for MEAM1, but T. vaporariorum bacteriocytes are genetically identical to other somatic cells of the insect, likely mediated by the degradation of maternal bacteriocytes in the embryo. These two alternative modes of transmission provide a first demonstration among insect symbioses that the cellular processes underlying vertical transmission of bacterial symbionts can diversify among related host species associated with a single lineage of symbiotic bacteria.
Strategic talent management systems and employee behaviors: the mediating effect of calling
Authors: Chen Shu‐Yuan , Lee Amber Yun‐Ping , Ahlstrom David
Published: July 2019

Developing and retaining talent is crucial in helping organizations compete effectively. However, how employers understand talent and thus invest appropriate resources to motivate and develop talented employees still requires considerable attention. This study argues that, differing from a generic HR system, the implementation of a more narrowly focused strategic talent management system (STMS) for investment in a talented group can craft the employees’ job interpretation in terms of employee calling. This can, in turn, further develop positive employee behaviors, including those of entrepreneurship and voice. In addition, a mediation effect of employee calling is examined in this study. Data were collected from 234 individuals in 45 firms across Taiwan. This study provides theoretical and empirical support for the effects of STMS. It also provides empirical evidence that employee calling is a key mediator for developing employees’ work behaviors. The practical implications identified are also an important reference for organizations.
Geographic information system‐based evaluation of spatial accessibility to maternal health facilities in Siaya County, Kenya
Authors: Ouko Jacob Joseph Ochieng , Gachari Moses Karoki , Sichangi Arthur Wafula , Alegana Victor
Published: July 2019

Maternal mortality is a major problem in middle‐income and low‐income countries, and the availability and accessibility of healthcare facilities offering safe delivery is important in averting maternal deaths. Siaya County, in Kenya, has one of the highest maternal mortality rates in the country—far more than the national average. This study aimed to evaluate geographic access to health facilities offering delivery services in Siaya County. A mixed‐methods approach incorporating geographic information system analysis and individual data from semi‐structured interviews was used to derive travel time maps to facilities using different travel scenarios: AccessMod5 and ArcGIS were used for these tasks. The derived maps were then linked to georeferenced household survey data in a multilevel logistic regression model in R to predict the probability of expectant women delivering in a health facility. Based on the derived travel times, 26 per cent (13,140) and 67 per cent (32,074) of the estimated 46,332 pregnant women could reach any facility within one and two hours, respectively, while walking with the percentage falling to seven per cent (3,415) and 20 per cent (8,845) when considering referral facilities. Motorised transport significantly increased coverage. The findings revealed that the predicted probability of a pregnant woman delivering in a health facility ranged between 0.14 and 0.86. Significant differences existed in access levels with transportation‐based interventions significantly increasing coverage. The derived maps can help health policy planners identify underserved areas and monitor future reductions in inequalities. This work has theoretical implications for conceptualising healthcare accessibility besides advancing the literature on mixed methodologies.
Anaerobic nitrate respiration in the aerobe Streptomyces coelicolor A3(2): helping maintain a proton gradient during dormancy
Authors: Sawers R. Gary , Fischer Marco , Falke Dörte
Published: July 2019

Respiratory nitrate reductases (Nar) catalyse the reduction of nitrate to nitrite, coupling this process to energy conservation. The obligate aerobic actinobacterium Streptomyces coelicolor synthesizes three Nar enzymes that contribute to maintenance of a membrane potential when either the mycelium or the spores become hypoxic or anoxic. No growth occurs under such conditions but the bacterium survives the lack of O2 by remaining metabolically active; reducing nitrate is one means whereby this process is aided. Nar1 is exclusive to spores, Nar2 to vegetative mycelium and Nar3 to stationary‐phase mycelium, each making a distinct contribution to energy conservation. While Nar2 and Nar3 appear to function like conventional menaquinol oxidases, unusually, Nar1 is completely dependent for its activity on a cytochrome bcc‐aa
3 oxidase supercomplex. This suggest that electrons within this supercomplex are diverted to Nar1 during O2 limitation. Receiving electrons from this supercomplex potentially allows nitrate reduction to be coupled to the Q‐cycle of the cytochrome bcc complex. This modification likely improves the efficiency of energy conservation, extending longevity of spores under O2 limitation. Knowledge gained on the bioenergetics of NO3− respiration in the actinobacteria will aid our understanding of how many microorganisms survive under conditions of extreme nutrient and energy restriction.
On the Perils of Structured Loans Financing in France and Italy
Authors: Oldani Chiara
Published: July 2019

The restructuring process of sovereign debt is not yet managed under common global rules; public debt stabilisation is an explicit policy goal in the EU, but cannot be achieved if local public authorities do not control their liabilities and connected risks. EU local administrations’ debt soared due to the economic downturn, reduced resources transferred from the central state and increasing expenses. After 2000, French and Italian local authorities extensively underwrote complex financial instruments, such as over the counter (OTC) interest rate and exchange rate derivatives and structured loans (i.e. loans with embedded derivatives) to manage their growing liabilities; the proliferation of derivatives among European public administrations has been favoured by the absence of proper disclosure and of monitoring procedures. Losses due to structured loans accumulated and in 2017 French local authorities asked for state rescue; similarly, some Italian regions and municipalities reported relevant losses. The reduction of financial risks can be achieved by improving information and transparency, by reducing moral hazard, and limiting ‘revolving doors’.
Overexpression of ANLN in lung adenocarcinoma is associated with metastasis
Authors: Xu Jie , Zheng Hong , Yuan Shuai , Zhou Bodong , Zhao Weipeng , Pan Yuan , Qi Daliang
Published: July 2019

Background

ANLN has been identified as an actin‐binding protein and previous studies have suggested that ANLN is associated with actin cytoskeletal dynamics. Lung adenocarcinoma is a poor prognosis tumor. Metastasis is a very common complication and is regarded as the main cause for an unsatisfactory treatment outcome. Whether ANLN is involved in the metastasis of lung adenocarcinoma is unknown.

Methods

We performed immunohistochemical staining and analyzed the correlation between the expression level and pathological parameters. We tested the migration and invasion of A549 and PC9 cell after interference with ANLN expression by Transwell and scratch wound healing assays. Protein expression of E‐cadherin, vimentin and N‐cadherin were detected using Western blotting and immunofluorescence staining. The same experiment was also tested after overexpression of ANLN.

Results

The metastasis of patients with high expression of ANLN was significantly more than that of patients with low expression of ANLN. In vitro, after interfering with ANLN expression, E‐cadherin and vimentin expression were increased and N‐cadherin expression was decreased in A549 and PC9 cells. Migration and invasion ability of A549 and PC9 cells were decreased,vice versa.

Conclusion

Our study suggests that the expression of ANLN in lung adenocarcinoma is associated with metastasis of cancer cells. ANLN may be involved in the metastasis of lung adenocarcinoma by promoting epithelial mesenchymal transformation of tumor cells.
A Deaf Lens: Adapting Video‐Cued Multivocal Ethnography for the “Kindergartens for the Deaf in Three Countries” Project
Authors: Valente Joseph Michael
Published: July 2019

This article reports on our use of a “deaf lens” in adapting video‐cued multivocal ethnography for the “Deaf Kindergartens in Three Countries: Japan, France, and the United States” project. Beginning with a discussion of how this “deaf lens” shaped the design of the study, research questions, and methodology, the article concludes with an example from our fieldwork illustrating the powerful potential of video‐cued multivocal ethnography for illuminating the lifeworlds of children, parent, and teacher informants.
From hierarchy to rivalry: Asian candidate evaluation in changing racial contexts
Authors: Go Min Hee
Published: July 2019

Existing studies on candidate evaluation have posited that racial cues would invoke negative attitudes toward outgroups, thus lowering support for minority candidates. However, recent studies have found that even implicit racial cues show no negative effect but actually work positively in favor of the minority candidates. In this study, I explore this puzzle by setting up a survey experiment that pairs an Asian candidate against competitors with varying racial backgrounds. Consistent with the existing evidence, I found that White voters tend to support an Asian candidate to a greater degree than a co‐ethnic, White competitor. However, departing from the previous studies that have explained this tendency as a reward for model minority, I argue that such a pattern is associated with reaffirming Whites’ ingroup identity in a racial hierarchy by compensating minorities. When the apparent racial hierarchy—White versus non‐White—is replaced with a minority‐only context, Whites no longer need to favor an Asian candidate and divide their support more evenly to the two minority candidates. I further show that this tendency is moderated by the intensity of their ingroup attitudes.
Impact of high‐altitude therapy on type‐2 immune responses in asthma patients
Authors: Boonpiyathad Tadech , Capova Gertruda , Duchna Hans‐Werner , Croxford Andrew L. , Farine Herve , Dreher Anita , Clozel Martine , Schreiber Juliane , Kubena Petr , Lunjani Nonhlanhla , Mirer David , Rückert Beate , Satitsuksanoa Pattraporn , Tan Ge , Groenen Peter M. A. , Bersuch Eugen , Akdis Mübeccel , Strasser Daniel S. , Renner Ellen D. , Akdis Cezmi A.
Published: July 2019

Background

Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high‐altitude treatment on the clinical and immunological response in asthma.

Methods

Twenty‐six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry.

Results

The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)‐expressing CD4+ and CD8+ T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2+ Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2‐expressing ILC2, CD4+ and CD8+ T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2+ Tregs which partially normalized during high‐altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2+ Treg cells in EA patients. Serum IL‐5 and IL‐13 decreased during climate treatment in asthma patients with high baseline levels.

Conclusions

Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions.
Toll‐like receptor 2 stimulation augments esophageal barrier integrity
Authors: Ruffner Melanie A. , Song Li , Maurer Kelly , Shi Lihua , Carroll Margaret C. , Wang Joshua X. , Muir Amanda B. , Spergel Jonathan M. , Sullivan Kathleen E.
Published: July 2019

Background

Germline‐encoded innate immune pattern recognition receptors (PRR) are expressed at epithelial surfaces and modulate epithelial defenses. Evidence suggests that stimulation of the Toll‐like receptor (TLR) family of PRR may regulate epithelial barrier integrity by upregulating tight junction (TJ) complex protein expression, but it is not known whether this mechanism is utilized in esophageal epithelial cells. TJ complex proteins maintain intact barrier function and are dysregulated in atopic disorders including eosinophilic esophagitis.

Methods

Pattern recognition receptors expression was assessed in EoE and control primary esophageal epithelial cells, demonstrating robust expression of TLR2 and TLR3. The three‐dimensional air‐liquid interface culture (ALI) model was used to test whether TLR2 or TLR3 stimulation alters epithelial barrier function using an in vitro model of human epithelium. Transepithelial electrical resistance (TEER) and FITC‐Dextran permeability were evaluated to assess membrane permeability. ALI cultures were evaluated by histology, immunohistochemistry, Western blotting, and chromatin immunoprecipitation (ChIP).

Results

TLR3 stimulation did not change TEER in the ALI model. TLR2 stimulation increased TEER (1.28‐ to 1.31‐fold) and decreased paracellular permeability to FITC‐Dextran, and this effect was abolished by treatment with anti‐TLR2 blocking antibody. TJ complex proteins claudin‐1 and zonula occludens‐1 were upregulated following TLR2 stimulation, and ChIP assay demonstrated altered histone 4 acetyl binding at the TJP1 enhancer and CLDN1 enhancer and promoter following zymosan treatment, implying the occurrence of durable chromatin changes.

Conclusions

Our findings implicate the TLR2 pathway as a potential regulator of esophageal epithelial barrier function and suggest that downstream chromatin modifications are associated with this effect.
Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events
Authors: Hawerkamp Heike C. , Kislat Andreas , Gerber Peter A. , Pollet Marius , Rolfes Katharina M. , Soshilov Anatoly A. , Denison Michael S. , Momin Afaque A. , Arold Stefan T. , Datsi Angeliki , Braun Stephan A. , Oláh Péter , Lacouture Mario E. , Krutmann Jean , Haarmann‐Stemmann Thomas , Homey Bernhard , Meller Stephan
Published: July 2019

Background

In recent years, the BRAF inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients’ quality of life and may lead to dose reduction or even cessation of anti‐tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib‐induced rashes have remained largely elusive.

Methods

In this study, we deployed immunohistochemistry, RT‐qPCR, flow cytometry, lymphocyte activation tests, and different cell‐free protein‐interaction assays.

Results

We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (eg, TNF) and chemokines (eg, CCL5). In line with these results, we observed an impaired expression of AhR‐regulated genes (eg, CYP1A1) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug‐specific T cells in respective patients.

Conclusion

Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point toward a potential role for topical AhR agonists in supportive cancer care.
Marijuana use and its influence on sperm morphology and motility: identified risk for fertility among Jamaican men
Authors: Carroll K. , Pottinger A. M. , Wynter S. , DaCosta V.
Published: July 2019

Background

The growing international movement legislating medical marijuana has brought renewed interest to the role of marijuana smoking on fertility potential. Although studies have identified that sperm quality can be compromised by marijuana use, little focus has been placed specifically on those trying to conceive. In this study, we aimed to clarify the impact of marijuana use in semen quality in men being investigated for assisted reproduction.

Materials and methods

We conducted a cross‐sectional study at a university‐based facility in Jamaica. Routine semen analyses were performed on 229 men ages 23–72 years who were new clients. Logistic regression analyses were performed in order to independently predict quantifiable measures of the impact of marijuana use. The main outcome measures were sperm motility, total motile spermatozoa and morphology.

Results

Overall, 47% of the participants reported marijuana use with 21% of these men reporting recent use. Regression analyses showed that recent use and users of large quantities of marijuana were 2.6 times (aOR = 2.6; 95% CI, 1.0–6.8, p = 0.044) and 4.3 times (aOR = 4.3; 95% CI, 1.1–15.9, p = 0.030) at greater risk of being diagnosed with abnormal motility (asthenozoospermia). Additionally, moderate quantity users were 3.4 times (aOR = 3.4; 95% CI, 1.5–7.9, p = 0.004) more likely to be diagnosed with abnormal morphology (teratozoospermia).

Discussion and conclusion

Recent use of marijuana as well as moderate to large quantities had an impact on sperm motility and morphology in men being investigated for infertility. We recommend therefore that men undergoing fertility investigations be routinely asked about their recreational use of marijuana and in particular recent and heavy users counselled to stop.
Efficacy and tolerability of sildenafil/l‐arginine combination relative to sildenafil alone in patients with organic erectile dysfunction
Authors: El‐Wakeel L. M. , Fouad F. A. , Saleem M. D. , Saber‐Khalaf M.
Published: July 2019

Background

Erectile dysfunction is defined as inability to achieve or maintain penile erection sufficient for sexual satisfaction. It is a serious problem that increases by age. The physiology of penile erection depends mainly on nitric oxide release.

Objectives

Compare the efficacy and safety of oral sildenafil 50 mg alone or in combination with l‐arginine 3 g/day orally on the treatment of erectile dysfunction.

Material and methods

Randomized controlled study with two parallel groups of erectile dysfunction patients; One group received sildenafil 50 mg every other day, while the other group received a combination of sildenafil (every other day)/l‐arginine on a daily base. Efficacy was assessed using International Index of Erectile Function‐5 score at the baseline and after 8 weeks. Side effects were evaluated across the two groups.

Results

The mean age was 56.3 ± 5 and 56.2 ± 4.4 years in sildenafil and combination groups, respectively. International Index of Erectile Function‐5 score was comparable between the two groups at the baseline (p value 0.44). International Index of Erectile Function‐5 score was improved from 15.3 ± 2.5 at baseline to 19.2 ± 2.3 after treatment, and this was statistically significant with p value <0.0001. The score was slightly better in combination group in which the average International Index of Erectile Function‐5 score was (19.8 ± 2.2) vs. (18.5 ± 2.3) in sildenafil group with p value 0.05. Side effects were more or less the same between the two groups except for gastritis which was more common on combination group.

Conclusion

Adding l‐arginine to sildenafil demonstrated more efficacy than sildenafil alone for treatment of erectile dysfunction patients.
Intermittent high‐flux albumin dialysis with continuous venovenous hemodialysis for acute‐on‐chronic liver failure and acute kidney injury
Authors: Niewinski Grzegorz , Raszeja‐Wyszomirska Joanna , Hrenczuk Marta , Rozga Agata , Malkowski Piotr , Rozga Jacek
Published: July 2019

Acute‐on‐chronic liver failure (ACLF) requiring intensive medical care and associated with acute kidney injury (AKI) has a mortality rate as high as 90% due to the lack of effective therapies. In this study, we assessed the effects of intermittent high‐flux single‐pass albumin dialysis (SPAD) coupled with continuous venovenous hemodialysis (CVVHD) on 28‐day and 90‐day survival and an array of clinical and laboratory parameters in patients with severe ACLF and renal insufficiency. Sixteen patients were studied. The diagnosis of ACLF and AKI was made in accordance with current EASL Clinical Practice Guidelines, including the recommendations of the International Club of Ascites. All patients received SPAD/CVVHD treatments as the blood purification therapy to support liver, kidneys, and other organs. Five patients were transplanted and 11 were not listed for transplantation because of active alcoholism. Data at the initiation of SPAD/CVVHD were compared with early morning data after the termination of the extracorporeal treatment phase. All patients had ACLF and renal insufficiency with 13/16 additionally fulfilling the AKI criteria. A total of 37 SPAD/CVVHD treatments were performed [2.3 ± 1.4]. The baseline MELD‐Na score was 37.6 ± 6.6 and decreased to 33.4 ± 8.7 after SPAD/CVVHD (P < 0.001). In parallel, the CLIF‐C ACLF grade and OF score, estimated at 28‐ and 90‐day mortality, AKI stage, hepatic encephalopathy grade, and liver function tests were lowered (P = 0.001–0.032). The 28‐ and 90‐day survivals were 56.2% overall and 53.8% in AKI. Survival in patients not transplanted (n = 11) was 45.4%. In patients with severe ACLF and AKI, the renal replacement therapy coupled with high‐performance albumin dialysis improved estimated 28‐ and 90‐day survival and several key clinical and laboratory parameters. It is postulated that these results may be further improved with earlier intervention and more SPAD treatments per patient. High‐performance albumin dialysis improves survival and key clinical and laboratory parameters in severe ACLF and AKI.
Increased risk of developing Crohn’s disease or ulcerative colitis in 17 018 patients while under treatment with anti‐TNFα agents, particularly etanercept, for autoimmune diseases other than inflammatory bowel disease
Authors: Korzenik Joshua , Larsen Michael Due , Nielsen Jan , Kjeldsen Jens , Nørgård Bente Mertz
Published: July 2019

Background

Anti‐TNFα agents have revolutionised management of chronic inflammatory diseases. Paradoxically, these agents might provoke development of de novo autoimmune diseases.

Aim

To examine whether there is an increased risk of developing Crohn's disease (CD) and ulcerative colitis (UC) while under treatment with anti‐TNFα agents for diseases other than inflammatory bowel disease (IBD)

Methods

A nationwide cohort study, based on Danish health registries, of all patients who utilised anti‐TNFα agents for non‐IBD indications. Included were patients, who had diseases for which anti‐TNFα agent is indicated (rheumatoid arthritis, psoriasis/psoriatic arthritis, ankylosing spondylitis, others). The observation period for development of de novo IBD started from 2004. Exposed patients had received at least one dose of anti‐TNFα.

Results

In total 17 018 individuals with autoimmune diseases were exposed to anti‐TNFα (the vast majority had infliximab, etanercept and adalimumab), and 63 308 individuals were not. Patients treated with etanercept had an increased risk of being diagnosed with CD and UC while under treatment, adjusted hazard ratio 2.0 [95% CI: 1.4‐2.8] and 2.0 [95% CI: 1.5‐2.8], respectively. The corresponding hazards ratios for infliximab were 1.3 [95% CI: 0.8‐2.2] and 1.0 [95% CI:0.6‐1.6], and for adalimumab 1.2 [95% CI: 0.8‐1.8] and 0.6 [95% CI: 0.3‐1.0].

Conclusions

Patients treated for autoimmune diseases with anti‐TNFα had an increased risk of being diagnosed with CD or UC while under treatment with etanercept. The nature of this association is uncertain. This finding has relevance to clinical care and insights into common mechanisms of the pathophysiology of these diseases.
The Persistence of the Black Colour in Magnetite‐Based Pigments in Prehispanic Ceramics of the Argentine North‐West
Authors: Puente V. , Porto López J. M. , Desimone P. M. , Botta P. M.
Published: July 2019

The persistence of the black colour in magnetite‐containing paints in polychrome ceramics of the Argentine North‐West processed under conditions considered as oxidant has generated questions about ancient production technologies. In this work, the thermal oxidation reaction of magnetite to hematite under different temperatures, atmospheres and physicochemical characteristics of the materials is experimentally evaluated. The causes of this behaviour are elucidated, and it is concluded that in the archaeological context, a double‐firing process was not necessary to achieve the coexistence of different colours.
Bridging Narratives: Predictors of Jewish American and Arab American Support for a Two‐State Solution to the Israeli–Palestinian Conflict
Authors: Ben Hagai Ella , Zurbriggen Eileen L.
Published: July 2019

In a survey study of Arab and Jewish Americans, we examined which beliefs best predicted support for a two‐state solution. We compared the role of a sense of collective victimhood, dehumanization of the outgroup, a zero‐sum view, and a monolithic narrative on the conflict. In both the Arab American and the Jewish American samples, framing the conflict in terms of a monolithic narrative played the strongest role in predicting rejection of a two‐state solution. On the other hand, when Jewish Americans agreed with the Palestinian narrative, that depicts the Palestinians as indigenous to the land but as dispossessed, they were more likely to support a two‐state solution. Similarly, when Arab Americans agreed with the Israeli narrative, in which Israelis want to live in peace but need to defend themselves, they were more likely to support a two‐state solution. In a second study, we examined if group values and concerns such as commitment to tikkun olam (commitment for justice for other minority groups) and concern with anti‐Semitism mediated between identification as Jewish and acceptance of the Palestinian narrative on the conflict. We found that concern with anti‐Semitism mediated between Jewish identity and rejection of the Palestinian narrative. On the other hand, grounding Jewish identity in values of tikkun olam mediated between Jewish identity and agreement with the Palestinian narrative. This research makes applied contributions by illuminating the key belief associated with support for peace among Arab and Jewish Americans. It also contributes to psychological theory on intergroup reconciliation by operationalizing and measuring the role of acknowledgement of the narrative of the other, group threat, and inclusive victimhood consciousness, in promoting peace.