bluuebunny/crossref_metadata_2025 huggingface dataset:
Programmable CRISPR interference for gene silencing using Cas13a in mosquitoes
Authors: Kulkarni Aditi , Yu Wanqin , Moon Alex , Pandey Ashmita , Hanley Kathryn A. , Xu Jiannong
Published: November 2019

In the CRISPR-Cas systems, Cas13a is an RNA-guided RNA nuclease specifically targeting single strand RNA. We developed a Cas13a mediated CRISPR interference tool to target mRNA for gene silencing in mosquitoes. The machinery was tested in two mosquito species. A Cas13a expressing plasmid was delivered to mosquitoes by intrathoracic injection, and Cas13a transcripts were detectable at least10 days post-delivery. In Anopheles gambiae, vitellogenin gene was silenced by Vg-crRNA injection two hours post-blood meal, which was accompanied by a significant reduction in egg production. In Aedes aegypti, the α- and δ-subunits of COPI genes were silenced by a post-blood meal crRNA injection, which resulted in mortality and fragile midguts, reproducing a phenotype reported previously. Co-silencing genes simultaneously is achievable when a cocktail of target crRNAs is given. No detectable collateral cleavages of non-target transcripts were observed in the study. This study adds a programmable CRISPR tool to manipulate RNA in mosquitoes.
Therapeutic efficacy of an immune stimulatory gene therapy strategy in a mouse model of high grade brainstem glioma
Authors: Mendez Flor M. , Kadiyala Padma , Nunez Felipe J. , Carney Stephen , Nunez Fernando , Gauss Jessica C. , Ravindran Ramya , Pawar Sheeba , Edwards Marta , Lowenstein Pedro R. , Castro Maria G.
Published: November 2019

Purpose

Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, ACVR1-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy.

Experimental Design

We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNAseq analysis on neurospheres (NS) harboring mACVR1. mACVR1 NS were implanted into the pons of immune competent mice to test the therapeutic efficacy and toxicity of immune stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 NS expressing the surrogate tumor antigen ovalbumin were generated to investigate if TK/Flt3L treatment induces the recruitment of tumor-antigen specific T cells.

Results

Histological analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 NS identified an increase in the transforming growth factor beta (TGF-β) signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in anti-tumor immunity, recruitment of anti-tumor specific T cells and increased median survival.

Conclusions

This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune stimulatory gene therapy targeting the hosts’ anti-tumor immune response inhibits tumor progression and increases median survival of mice bearing mACVR1 tumors.

Translational Relevance

The therapeutic efficacy of anti-DIPG immune responses is limited due to a low number of immune cells in the tumor microenvironment. We have uncovered a novel treatment strategy that utilizes adenoviral delivery of therapeutic genes, thymidine kinase (TK) and fms tyrosine kinase 3 ligand (Flt3L) into the tumor, eliciting a reprograming of the host’s own immune system to recognize and kill tumor cells. We demonstrate that TK/Flt3L therapy generates an effective anti-tumor response and can be safely delivered into the brainstem. This treatment approach could provide a novel translational approach towards potentiating an anti-DIPG immune response to overcome the current limitations in the treatment of patients with DIPG.
The extended recovery ring stage survival assay provides superior prediction of patient clearance half life and increases throughput
Authors: Davis Sage Z. , Singh Puspendra P. , Vendrely Katelyn M. , Shoue Douglas A. , Checkley Lisa A. , McDew-White Marina , Button-Simons Katrina A. , Cassady Zione , Sievert Mackenzie A.C. , Foster Gabriel J. , Nosten François H. , Anderson Timothy J.C. , Ferdig Michael T.
Published: November 2019

Background

Tracking and understanding artemisinin resistance is key for preventing global setbacks in malaria eradication efforts. The ring-stage survival assay (RSA) is the current gold standard for in vitro artemisinin resistance phenotyping. However, the RSA has several drawbacks: it is relatively low throughput, has high variance due to microscopy readout, and correlates poorly with the current benchmark for in vivo resistance, patient clearance half-life post-artemisinin treatment. Here a modified RSA is presented, the extended Recovery Ring-stage Survival Assay (eRRSA), using 15 cloned patient isolates from Southeast Asia with a range of patient clearance half-lives, including parasite isolates with and without kelch13 mutations.

Methods

P. falciparum cultures were synchronized with single layer Percoll during the schizont stage of the erythrocytic cycle. Cultures were left to reinvade to early ring-stage and parasitemia was quantified using flow cytometry. Cultures were diluted to 2% hematocrit and 0.5% parasitemia in a 96-well plate to start the assay, allowing for increased throughput and decreased variability between biological replicates. Parasites were treated with 700nM of dihydroartemisinin or an equivalent amount of dimethyl sulfoxide (DMSO) for 6 h, washed three times in drug-free media, and incubated for 66 or 114 h, when samples were collected and frozen for PCR amplification. A SYBR Green-based quantitative PCR method was used to quantify the fold-change between treated and untreated samples.

Results

15 cloned patient isolates from Southeast Asia with a range of patient clearance half-lives were assayed using the eRRSA. Due to the large number of pyknotic and dying parasites at 66 h post-exposure (72 h sample), parasites were grown for an additional cell cycle (114 h post-exposure, 120 h sample), which drastically improved correlation with patient clearance half-life compared to the 66 h post-exposure sample. A Spearman correlation of 0.8393 between fold change and patient clearance half-life was identified in these 15 isolates from Southeast Asia, which is the strongest correlation reported to date.

Conclusions

eRRSA drastically increases the efficiency and accuracy of in vitro artemisinin resistance phenotyping compared to the traditional RSA, which paves the way for extensive in vitro phenotyping of hundreds of artemisinin resistant parasites.
Unveiling the physiological mechanisms that drive the emergence of antibiotic resisters from antibiotic persister population of mycobacteria
Authors: Jakkala Kishor , Sharan Deepti , Nair Rashmi Ravindran , Paul Avraneel , Pradhan Atul , Ajitkumar Parthasarathi
Published: November 2019

The physiological mechanisms behind the emergence of antibiotic-resistant bacteria from their antibiotic-persister population are beginning to be explored. Here we delineate the sequential physiological events that drive the emergence of rifampin-resistantrpoBmutants from rifampin-persister population of mycobacteria during prolonged exposure. The rifampin-persister population generated elevated levels of hydroxyl radical, which inflicted mutations, enabling regrowth of the persister cells to form multi-septated, multi-nucleated elongated cells. These cells, through multiple divisions, produced multiple sister-daughter cells, causing an abrupt, unexpectedly high increase of rifampin-resistant colonies. Similar response was observed against moxifloxacin also. Earlier studies on the rifampin/moxifloxacin-exposed laboratory/clinicalM. tuberculosisstrains fromin-vitrocultures and infected mouse-lung also showed cfu spurt, but went unnoticed/unreported. It is likely that these sequential physiological events may be driving the emergence of antibiotic-resistant tubercle bacilli in TB patients also.Escherichia colialso has been found to respond similarly against subminimal inhibitory concentrations of ciprofloxacin. Thus, the present findings attain broad significance as a general physiological mechanism used by diverse bacterial genera to emerge as drug-resistant strains against antibiotics.
bsAS, an antisense long non-coding RNA, controls cell fate through regulation ofblistered/DSRFisoform expression
Authors: Pérez-Lluch Sílvia , Breschi Alessandra , Klein Cecilia C. , Ruiz-Romero Marina , Abad Amaya , Palumbo Emilio , Bekish Lyazzat , Arnan Carme , Guigó Roderic
Published: November 2019

Natural Antisense Transcripts (NATs) are long non-coding RNAs (lncRNAs) that overlap coding genes in the opposite strand. NATs roles have been related to gene regulation through different mechanisms, including post-transcriptional RNA processing. With the aim to identify NATs with potential regulatory function during fly development, we generated RNA-Seq data in eye-antenna, leg, and wing at third instar larvae. Among the candidate NATs, we foundbsAS, antisense tobs/DSRF, a gene involved in wing development and neural processes. Through the analysis of the RNA-Seq data, we found that these two different functions are carried out by the two different protein isoforms encoded in thebsgene. We also found that the usage of these isoforms is regulated bybsAS. This regulation is essential for the correct determination of cell fate duringDrosophiladevelopment, asbsASknockouts show highly aberrant phenotypes.bsregulation bybsASis mediated by the specific physical interaction of thebsASpromoter with the promoters ofbs, and it likely involves a mechanism, where expression ofbsASleads to the collision of RNA polymerases acting in opposite directions, preventing the elongation of the longer isoforms ofbs, the ones carrying the neural related functions. Evolutionary analysis suggests that thebsASNAT emerged simultaneously to the long-short isoform structure ofbs, preceding the emergence of wings in insects, and maybe related to regulation of neural differentiation.
Osmotic stress-induced, rapid clustering of IGF2BP proteins nucleates stress granule assembly
Authors: Zeng Wei-jie , Lu Chuxin , Shi Yuanyuan , Chen Xinxin , Yao Jie
Published: November 2019

Stress granules (SGs) are formed in the cytoplasm by liquid-liquid phase separation (LLPS) of translationally-stalled mRNA and RNA-binding proteins during stress response. Understanding the mechanisms governing SG assembly requires imaging SG formation in real time. Here we used live cell imaging and super-resolution imaging to visualize SG assembly in human cells. We found that IGF2BP proteins formed microscopically visible clusters almost instantaneously upon osmotic stress, prior to the recruitment of G3BP1 and TIA1. The rapid clustering of IGF2BP1 was ATP-independent and was mediated by its KH3/4 di-domains and an intrinsically disordered region (IDR), whereas ATP depletion inhibited the recruitment of G3BP1 and TIA1. Moreover, we detected cytoplasmic clusters of IGF2BP1 below the optical resolution in normal cells and found IGF2BP1 forming a dense granule associated with multiple clusters of poly(A) mRNA in mature SGs. Thus, ATP-independent, rapid clustering of IGF2BP nucleates SG assembly during osmotic stress.
Chromatin-sensitive cryptic promoters putatively drive expression of alternative protein isoforms in yeast
Authors: Wei Wu , Hennig Bianca P. , Wang Jingwen , Zhang Yujie , Piazza Ilaria , Pareja Sanchez Yerma , Chabbert Christophe D. , Adjalley Sophie H. , Steinmetz Lars M. , Pelechano Vicent
Published: November 2019

Cryptic transcription is widespread and generates a heterogeneous group of RNA molecules of unknown function. To improve our understanding of cryptic transcription, we investigated their transcription start site (TSS) usage, chromatin organization, and posttranscriptional consequences in Saccharomyces cerevisiae. We show that TSSs of chromatin-sensitive internal cryptic transcripts retain comparable features of canonical TSSs in terms of DNA sequence, directionality, and chromatin accessibility. We define the 5′ and 3′ boundaries of cryptic transcripts and show that, contrary to RNA degradation–sensitive ones, they often overlap with the end of the gene, thereby using the canonical polyadenylation site, and associate to polyribosomes. We show that chromatin-sensitive cryptic transcripts can be recognized by ribosomes and may produce truncated polypeptides from downstream, in-frame start codons. Finally, we confirm the presence of the predicted polypeptides by reanalyzing N-terminal proteomic data sets. Our work suggests that a fraction of chromatin-sensitive internal cryptic promoters initiates the transcription of alternative truncated mRNA isoforms. The expression of these chromatin-sensitive isoforms is conserved from yeast to human, expanding the functional consequences of cryptic transcription and proteome complexity.
Workforce productivity evaluation of the US construction industry from 2006 to 2016
Authors: Li Yulong , Lin Jie , Cui Zihan , Wang Chao , Li Guijun
Published: November 2019

Purpose

Currently, there is a dearth of research studies regarding macro analysis of the workforce productivity of the US construction industry. The purpose of this paper is to calculate the workforce productivity changes of the US construction industry from 2006 to 2016, with the number of laborers as input and value of construction industry as output.

Design/methodology/approach

The present study introduced the data envelopment analysis (DEA) based Malmquist productivity index model to measure the workforce productivity of the US construction industry from 2006 to 2016.

Findings

The results indicated that the workforce productivity of the US construction industry experienced a continuous decline, except for the increases from 2011 to 2013 and from 2014 to 2015. It was also shown that there were gaps in the workforce productivity development level among all states and nine regions in the US construction industry. Besides, the relationship between workforce productivity and four aspects, including real estate price, workforce, climate distribution and economic factors, was analyzed.

Research limitations/implications

The calculation of the productivity of the US construction industry is based on the premise that the external environment is fixed and unchanged from 2006 to 2016, but the multi-level DEA model for further calculation is required for obtaining more effective conclusions.

Social implications

This paper measures the workforce productivity of the US construction industry over the past 11 years, which added latest analysis and knowledge into the construction industry, providing decision-makers with advice and data support to formulate policies to improve workforce productivity.

Originality/value

This study provided both government decision-makers and industrial practitioners with important macro background environment information, which will facilitate the improvement of workforce productivity in the construction industry in different regions of the US.
Smart libraries: an emerging and innovative technological habitat of 21st century
Authors: Gul Sumeer , Bano Shohar
Published: November 2019

Purpose

The purpose of this paper is to discuss the emerging and innovative technologies which integrate together to form smart libraries. Smart libraries are the new generation libraries, which work with the amalgamation of smart technologies, smart users and smart services.

Design/methodology/approach

An extensive review of literature on “smart libraries” was carried to ascertain the emerging technologies in the smart library domain. Clarivate Analytic’s Web of Science and Sciverse Scopus were explored initially to ascertain the extent of literature published on Smart Libraries and their varied aspects. Literature was searched against various keywords like smart libraries, smart technologies, Internet of Things (IoT), Electronic resource management (ERM), Data mining, Artificial intelligence (AI), Ambient intelligence, Blockchain Technology and Augmented Reality. Later on, the works citing the literature on Smart Libraries were also explored to visualize a broad spectrum of emerging concepts about this growing trend in libraries.

Findings

The study confirms that smart libraries are becoming smarter with the emerging smart technologies, which enhances their working capabilities and satisfies the users associated with them. Implementing the smart technologies in the libraries has bridged the gap between the services offered by the libraries and the rapidly changing and competing needs of the humans.

Practical implications

The paper highlights the emerging smart technologies in smart libraries and how they influence the efficiency of libraries in terms of users, services and technological integration.

Originality/value

The paper tries to highlight the current technologies in the smart library set-ups for the efficient working of library set-ups.
Interest-free microfinance in India
Authors: Shaik Mohammed Wasiullah , Waheed Khalid
Published: November 2019

Purpose

The purpose of this study is to understand the operations of interest-free microfinance institutions, find the issues and recommend possible solutions in the Indian context.

Design/methodology/approach

This paper is based on the case study of Sanghamam Multistate Cooperative Credit Society. This research uses both primary and secondary data. The institution is assessed in terms of two major performance aspects, namely, outreach indicators and financial performance indicators. A brief comparative study of Sanghamam with the aggregate performance of the Indian microfinance industry has also been included.

Findings

It is found that Sanghamam has been successfully providing interest-free microfinance services in India. The performance of Sanghamam on selected industry benchmarks is in line with the performance of the Indian microfinance industry. However, a few issues such as potential liquidity risk, lower penetration in the poorer sections of the population, Shariah issues in the method of determination of service charges on demand loans and in the structure of group deposit scheme and profit-sharing business loans have been highlighted.

Research limitations/implications

Sanghamam is evaluated from only outreach and financial performance aspects and not from the aspect of the impacts of its services.

Practical implications

This study would help in documenting the operations of Sanghamam. Moreover, the recommendations provided, if implemented, would help Sanghamam in further growth.

Social implications

This study would help create awareness in the society about the practices of interest-free microfinance.

Originality/value

This paper highlights the interest-free microfinance practices in India that have not received the needed attention. The authors have discussed the key issues related to the interest free microfinance and recommended the possible solutions.
Effect of current pulsing on super 304HCu weld joints
Authors: M. Vinoth Kumar , V. Balasubramanian
Published: November 2019

Purpose

Super 304HCu super austenitic stainless steel tubes containing 2.3 to 3 (Wt.%) of copper (Cu) is used in superheaters and reheater tubings of nuclear power plants. In general, austenitic stainless steels welded by conventional constant current gas tungsten arc welding (CC-GTAW) produce coarse columnar grains, alloy segregation and may result in inferior mechanical properties. Pulsed current gas tungsten arc welding (PC-GTAW) can control the solidification structure by altering the prevailing thermal gradients in the weld pool.

Design/methodology/approach

Super 304HCu tubes of Ø 57.1 mm and the wall thickness of 3.5 mm were autogenously welded using CC and PC-GTAW processes. Joints are characterized using optical microscopy, electron microscopy, energy dispersive spectroscopy and electron backscatter diffraction (EBSD) techniques. Hot tensile properties of the weld joints were evaluated and correlated with their microstructural features.

Findings

Current pulsing in GTAW has resulted in minimal eutectic film segregation, lower volume % of delta ferrite and appreciable improvement in tensile properties than CC-GTAW joints.

Originality/value

The EBSD boundary map and inverse pole orientation map of Super 304HCu weld joints evidence the grain refinement and much frequent high angle grain boundaries achieved using weld current pulsing.
When to vaccinate a fluctuating wildlife population: Is timing everything?
Authors: Schreiner Courtney L. , Nuismer Scott L. , Basinski Andrew J.
Published: November 2019

Wildlife vaccination is an important tool for managing the burden of infectious disease in human populations, domesticated livestock and various iconic wildlife. Although substantial progress has been made in the field of vaccine designs for wildlife, there is a gap in our understanding of how to time wildlife vaccination, relative to host demography, to best protect a population.

We use a mathematical model and computer simulations to assess the outcomes of vaccination campaigns that deploy vaccines once per annual population cycle.

Optimal timing of vaccination is an important consideration in animals with short to intermediate life spans and a short birthing season. Vaccines that are deployed shortly after the birthing season best protect the host population.

The importance of timing is greater in wildlife pathogens that have a high rate of transmission and a short recovery period. Vaccinating at the end of the birthing season best reduces the mean abundance of pathogen‐infected hosts. Delaying vaccination until later in the year can facilitate pathogen elimination.

Policy Implications. Tuning wildlife vaccination campaigns to host demography and pathogen traits can substantially increase the effectiveness of a campaign. Our results suggest that, for a fluctuating population, vaccinating at, or shortly after, the end of the birthing season, best protects the population against an invading pathogen. If the pathogen is already endemic, delaying vaccination until after the birthing season is over can help facilitate pathogen elimination. Our results highlight the need to better understand and predict host demography in wildlife populations that are targeted for vaccination.
Brexit, Cabinet Norms and the Ministerial Code: Are we Living in a post‐Nolan Era?
Authors: Andrews Leighton
Published: November 2019

The Nolan Report will celebrate its twenty‐fifth anniversary in 2020, and for most of this last quarter‐century, it has provided the underlying ethical basis for public life in the United Kingdom. However, its principles are now being called into question in a number of areas, following the Conservative government’s loss of its parliamentary majority in the 2017 election, with the interests of party taking precedence over adherence to both the spirit and the codified practical implementation of some of the ultimate outcomes of Nolan, namely the Ministerial Code and the Commissioner for Parliamentary Standards. This article argues, with explicit evidence and examples, that ministerial conduct which would not have been tolerated before 2017 is now being routinely ignored in the interest of maintaining party unity in order to deliver some form of Brexit. The article concludes by asking whether Nolan norms still command consensus post‐Brexit.
Components of disability exclusion: Discrimination, avoidance and accessibility in later life
Authors: Temple Jeromey B. , Kelaher Margaret , Utomo Ariane , Williams Ruth , Brooke Libby
Published: November 2019

Objective

To examine the prevalence and context of disability exclusion reported by people with disability, with and without communication and mobility problems.

Methods

The 2015 Survey of Disability Ageing and Carers was used to measure the prevalence of reported exclusion. Tests of proportions were used to examine differences in prevalence rates. Proportional Venn diagrams were used to examine the intersection of measures of exclusion.

Results

Approximately 53% of those with a communication or mobility difficulty reported at least one measure of exclusion. Among this group, 7% reported an instance of discrimination, 44% reported avoidance, and 29% reported an accessibility problem. The levels of discrimination and avoidance for those without communication or mobility difficulties were approximately half this level (16% avoidance and 3% discrimination). Avoidance and discrimination reduced with age, but accessibility was age‐invariant. Exclusion measures intersected and occurred in a variety of contexts.

Conclusion

Despite protections provided in Australian law, disability exclusion persists and is high among those with communication and mobility difficulties.
The Anthropology of Bees
Authors: Wood John Colman
Published: November 2019

For the past six years I’ve been studying beekeepers in Buncombe County, North Carolina. My interest in beekeeping is part of a larger project on place and identity. “The Anthropology of Bees” grew out of my getting to know one of those beekeepers who had a progressive, ultimately fatal disease. The man in the story is not that man. Nevertheless, the story aims to give readers a sense of what it was like to be him. His interest in and care for bees enlivened him even as his life diminished. As he took care of the bees, the bees drew him into the world from which he might otherwise have withdrawn. The mechanics of his disease are less important here than his experience of it, his sense of life in the shadows.
Cold‐worked and annealed bronze objects and relevant motif techniques in the Chinese Bronze Age: Analysis of bronze sheets found at Songjia cemetery in Shaanxi, China
Authors: Haichao L. , Siran L. , Jianli C. , Jianfeng C. , Xingshan L. , Jianrong C. , Yuewen G. , Xingrui L. , Yuxuan H.
Published: November 2019

Six thin Chinese bronze chariot accessory sheets from Songjia cemetery in Shaanxi province were dated to the late Western Zhou dynasty (ninth to eighth centuries bce) and analysed for their elemental composition and motif techniques. The objects were cold worked and annealed with embossed motifs and carved lines. This is the only case of cold working and annealing with embossed motifs and carved lines in China; these techniques may have come from or been influenced by other cultures. These findings are important for revealing the development of the cold‐working, annealing techniques and relevant motif techniques in China.
Roman pottery production in Civitas Tungrorum, central Belgium, during the first–third centuries ce
Authors: Borgers B. , Quinn P. , Degryse P. , De Bie M. , Welkenhuysen K.
Published: November 2019

Aspects of Roman pottery production at the workshops of Kontich, Tienen, Rumst, Grobbendonk and Clavier‐Vervoz in the Civitas Tungrorum of central Belgium are explored. A total of 150 wasters from five sites were studied macroscopically, as well as via a combination of thin‐section petrography, geochemistry and scanning electron microscopy, in order to gain insights into ceramic technology and aspects of the organization of production. Particular emphasis was given to the individual technological sequences and shared strategies of raw material selection, paste preparation and firing employed at the five adjacent sites. The integration of petrographic and geochemical data permitted the establishment of compositional reference groups for the Roman kiln sites of Civitas Tungrorum, which can be used to track their products within the surrounding landscape.
Plant indicators for Folic Histosols in mountain forests of the Calcareous Alps
Authors: Olleck Michelangelo , Reger Birgit , Ewald Jörg
Published: November 2019

Questions

Although thick forest floors overlying unweathered bedrock are important resources for mountain forests' functioning, their actual distribution is poorly known and difficult to delimit in the field. We therefore asked: (a) What is the specific composition of vegetation growing on Folic Histosols; (b) can indicator plants be used to detect Folic Histosols in mountain forests; (c) what do functional traits of plant indicators tell about the ecological properties of Folic Histosols?

Location

Northern Calcareous Alps, south Germany.

Methods

Based on representative stratified sampling of joint vegetation plots and soil profile descriptions, we estimated the frequency and thickness of Folic Histosols, determined the proportion of compositional variation specifically attributable to forest floor thickness using ordination, applied Indicator Species Analysis and searched for typical traits and ecological requirements of indicator species.

Results

The co‐existence of acidophilic and calciphytic plants is typical for the tessellated occurrence and the successional origin of Folic Histosols. In the study region, the detection of Folic Histosols on pure limestone or dolomite by ground vegetation works very well. Particularly acidophilic plants are suitable indicators for thick forest floors. The indicator value of bryophytes and Ericaceae for Folic Histosols is likely related to the colonization of rotten wood. Folic Histosol indicator species are widely spread in the allocation to sociology group, which ranges from open landscapes to dark forests and reflects successional origin.

Conclusions

In mountain forests on carbonate bedrock, thick humus layers often occur next to bare rock. This tessellated structure can also be detected in the ground vegetation, where acidophilic and calciphytic plants occur side by side. Thick Folic Histosols in late successional forests are dominated by acidophilic plants colonizing rotten wood. Thus, the detection of Folic Histosols by understorey species is an easy and cost‐effective possibility and one key to protect these vulnerable forest sites.
Bayesian shrinkage estimation of high dimensional causal mediation effects in omics studies
Authors: Song Yanyi , Zhou Xiang , Zhang Min , Zhao Wei , Liu Yongmei , Kardia Sharon L. R. , Roux Ana V. Diez , Needham Belinda L. , Smith Jennifer A. , Mukherjee Bhramar
Published: November 2019

Causal mediation analysis aims to examine the role of a mediator or a group of mediators that lie in the pathway between an exposure and an outcome. Recent biomedical studies often involve a large number of potential mediators based on high‐throughput technologies. Most of the current analytic methods focus on settings with one or a moderate number of potential mediators. With the expanding growth of ‐omics data, joint analysis of molecular‐level genomics data with epidemiological data through mediation analysis is becoming more common. However, such joint analysis requires methods that can simultaneously accommodate high‐dimensional mediators and that are currently lacking. To address this problem, we develop a Bayesian inference method using continuous shrinkage priors to extend previous causal mediation analysis techniques to a high‐dimensional setting. Simulations demonstrate that our method improves the power of global mediation analysis compared to simpler alternatives and has decent performance to identify true nonnull contributions to the mediation effects of the pathway. The Bayesian method also helps us to understand the structure of the composite null cases for inactive mediators in the pathway. We applied our method to Multi‐Ethnic Study of Atherosclerosis and identified DNA methylation regions that may actively mediate the effect of socioeconomic status on cardiometabolic outcomes.
Added value of diffusion‐weighted images and dynamic contrast enhancement in multiparametric magnetic resonance imaging for the detection of clinically significant prostate cancer in the PICTURE trial
Authors: Eldred‐Evans David , Neves Joana B. , Simmons Lucy A.M. , Kanthabalan Abi , McCartan Neil , Shah Taimur T. , Arya Manit , Charman Susan C. , Freeman Alex , Moore Caroline M. , Punwani Shonit , Emberton Mark , Ahmed Hashim U.
Published: November 2019

Objective

To determine the additional diagnostic value of diffusion‐weighted imaging (DWI) and dynamic contrast‐enhanced imaging (DCE) in men requiring a repeat biopsy within the PICTURE study.

Patients and Methods

PICTURE was a paired‐cohort confirmatory study in which 249 men who required further risk stratification after a previous non‐magnetic resonance imaging (MRI)‐guided transrectal ultrasonography‐guided biopsy underwent a 3‐Tesla (3T) multiparametic (mp)MRI consisting of T2‐weighted imaging (T2W), DWI and DCE, followed by transperineal template prostate mapping biopsy. Each mpMRI was reported using a LIKERT score in a sequential blinded manner to generate scores for T2W, T2W+DWI and T2W+DWI+DCE. Area under the receiver‐operating characteristic curve (AUROC) analysis was performed to compare the diagnostic accuracy of each combination. The threshold for a positive mpMRI was set at a LIKERT score ≥3. Clinically significant prostate cancer was analysed across a range of definitions including UCL/Ahmed definition 1 (primary definition), UCL/Ahmed definition 2, any Gleason ≥3 + 4 and any Gleason ≥4 + 3.

Results

Of 249 men, sequential MRI reporting was available for 246. There was a higher rate of equivocal lesions (44.6%) using T2W alone compared to the addition of DWI (23.9%) and DCE (19.8%). Using the primary definition of clinically significant disease, there was no significant difference in the overall accuracy between T2W, with an AUROC of 0.74 (95% confidence interval [CI] 0.68–0.80), T2W+DWI at 0.76 (95% CI 0.71–0.82), and T2W+DWI+DCE, with an AUROC of 0.77 (95% CI 0.71–0.82; P = 0.55). The AUROC values remained comparable using other definitions of clinically significant disease including UCL/Ahmed definition 2 (P = 0.79), Gleason ≥3 + 4 (P = 0.53) and Gleason ≥4 + 3 (P = 0.53).

Conclusions

Using 3T MRI, a high level of diagnostic accuracy can be achieved using T2W as a single parameter in men with a prior biopsy; however, such a strategy can lead to a higher rate of equivocal lesions.
IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations
Authors: Yang Rui Ryan , Shi Zhi‐feng , Zhang Zhen‐yu , Chan Aden Ka‐Yin , Aibaidula Abudumijiti , Wang Wei‐wei , Kwan Johnny Sheung Him , Poon Wai Sang , Chen Hong , Li Wen‐cai , Chung Nellie Yuk‐Fei , Punchhi Gopika , Chu William Ching‐Yuen , Chan Ivan Sik‐Hei , Liu Xian‐zhi , Mao Ying , Li Kay Ka‐Wai , Ng Ho‐Keung
Published: November 2019

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH‐mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high‐risk group also demonstrated a shorter PFS compared to intermediate‐ (P = 0.036) and low‐risk (P < 0.0001) groups. One limitation of this study is the relatively short follow‐up period, a common confounding factor for studies on low‐grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.
Heterogeneity of microglia and their differential roles in white matter pathology
Authors: Lee Janice , Hamanaka Gen , Lo Eng H. , Arai Ken
Published: November 2019

Microglia are resident immune cells that play multiple roles in central nervous system (CNS) development and disease. Although the classical concept of microglia/macrophage activation is based on a biphasic beneficial‐versus‐deleterious polarization, growing evidence now suggests a much more heterogenous profile of microglial activation that underlie their complex roles in the CNS. To date, the majority of data are focused on microglia in gray matter. However, demyelination is a prominent pathologic finding in a wide range of diseases including multiple sclerosis, Alzheimer's disease, and vascular cognitive impairment and dementia. In this mini‐review, we discuss newly discovered functional subsets of microglia that contribute to white matter response in CNS disease onset and progression. Microglia show different molecular patterns and morphologies depending on disease type and brain region, especially in white matter. Moreover, in later stages of disease, microglia demonstrate unconventional immuno‐regulatory activities such as increased phagocytosis of myelin debris and secretion of trophic factors that stimulate oligodendrocyte lineage cells to facilitate remyelination and disease resolution. Further investigations of these multiple microglia subsets may lead to novel therapeutic approaches to treat white matter pathology in CNS injury and disease.
Safety of direct‐acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients
Authors: Santeusanio Andrew D. , Weinberg Alan D. , Florman Sander S. , Schiano Thomas D.
Published: November 2019

Despite increasingly widespread utilization of direct‐acting oral anticoagulants (DOACs), there remains limited experience with the use of these agents following liver transplantation. We performed a single‐center, retrospective review of liver transplant recipients prescribed DOACs or warfarin between January 2014 and January 2018. Patients receiving DOACs were matched with warfarin‐treated controls based on discrete clinical parameters and followed from the time of anticoagulant prescription, until treatment discontinuation or study conclusion. The primary endpoint for this review was the incidence of clinically relevant major or non‐major bleeding among the treatment groups. Twenty‐seven patients prescribed DOACs were identified for inclusion in the review, of which 20 could be matched with suitable warfarin controls. At the conclusion of the study, warfarin‐treated patients had a significantly higher incidence of clinically relevant bleeding (45% vs 15%; P = .01). No statistically significant differences were found in the rate of new or recurrent thrombotic events. Multivariable logistic regression demonstrated that warfarin treatment was associated with a significantly higher odds of a bleeding event compared to treatment with a DOAC (OR = 6.9; 95% CI, 1.1‐44.6). DOAC use appears relatively safe compared with warfarin in select liver transplant recipients. Patient‐specific factors still bear consideration when selecting between the various anticoagulant options.
Participation and Receptivity in the Art Museum – A Phenomenological Exposition
Authors: Høffding Simon , Rung Mette , Roald Tone
Published: November 2019

There is a powerful trend in museums today of asking visitors to participate in the exhibitions, co‐create content, and to be active and engage with one another in the museum space. While welcoming the participatory agenda as an initiative of democratizing art museums, we argue in this paper that the rise of the participatory agenda also redefines the purpose of the art museum in a way that risks overlooking the kinds of experiences people undergo in art museums. Based on qualitative and phenomenologically inspired interviews with museum visitors, we present a sketch of a class of aesthetic experiences that ought to be taken into consideration in curatorial practices. Developing a picture of the phenomenology of aesthetic experience, we argue that such experiences should be taken into account when considering the question of the purpose of the art museum.
Diagnosis and treatment of xerosis cutis – a position paper
Authors: Augustin Matthias , Wilsmann‐Theis Dagmar , Körber Andreas , Kerscher Martina , Itschert Götz , Dippel Michaela , Staubach Petra
Published: November 2019

Background and rationale

Xerosis cutis (also referred to as xeroderma, dry skin, asteatosis) affects more than 10 million individuals in Germany. It is among the most common dermatological diagnoses and a cardinal symptom of many dermatological, internal and neurological diseases. Even though it has been established that basic skin care plays a significant role in the management of patients with xerosis cutis, there are as yet no evidence‐based algorithms for diagnosis and treatment.

Objective

The present position paper provides physicians across all specialties with a practical, symptom‐based approach to the prevention, diagnosis and treatment of xerosis cutis.

Methods

Within a structured decision‐making process, a panel of experienced dermatologists first defined questions relevant to everyday clinical practice, which were then addressed by a systematic review of the literature. Based on the evidence available as well as expert consensus, diagnostic and treatment algorithms were subsequently developed and agreed upon.

Results

Xerosis cutis is generally diagnosed on clinical grounds. Possible trigger factors must be avoided, and comorbidities should be adequately and specifically treated. Suitable skin care products should be chosen with a view to improving skin hydration and restoring its barrier function. They should therefore contain both rehydrating and lipid‐replenishing components. The “drier” the skin appears, the greater the lipid content should be (preferably using water‐in‐oil formulations). The choice of ingredients is based on a patient's individual symptoms, such as scaling (e.g., urea), fissures/rhagades (e.g., urea or dexpanthenol), erythema (e.g., licochalcone A) and pruritus (e.g., polidocanol). Other factors to be considered include the site affected and patient age. Ingredients or rather combinations thereof for which there is good clinical evidence should be preferentially used. The best evidence by far is available for urea, whose efficacy in the treatment of xerosis is further enhanced by combining it with other natural moisturizing components and ceramides. The “xerosimeter” is a tool developed in an effort to facilitate patient management and for training purposes. It not only includes practical tools for diagnosis and follow‐up but also a classification of ingredients and a structured treatment algorithm.

Conclusion

The structured symptom‐ and evidence‐based approach proposed herein contains a road map for diagnosis and treatment of xerosis cutis. It aims to raise awareness in terms of prevention and early treatment of this condition and may thus improve quality of life and prevent potential sequelae.
Successful balloon enteroscope‐guided pancreatic ductal stenting of stricture at pancreaticojejunal anastomosis using chromoendoscopy with indigo carmine
Authors: Kin Toshifumi , Takahashi Kuniyuki , Katanuma Akio
Published: November 2019

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Endoscopic ultrasonography‐guided hepaticogastrostomy with novel two‐step puncture technique following peroral cholangioscopy‐assisted stone removal
Authors: Mukai Shuntaro , Tsuchiya Takayoshi , Itoi Takao
Published: November 2019

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Endoscopic selective muscular dissection for clinical submucosal invasive early gastric cancer
Authors: Yabuuchi Yohei , Takizawa Kohei , Ono Hiroyuki
Published: November 2019

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Persistent atrial fibrillation in heart failure with preserved ejection fraction: Prognostic relevance and association with clinical, imaging and invasive haemodynamic parameters
Authors: Schönbauer Robert , Duca Franz , Kammerlander Andreas A. , Aschauer Stefan , Binder Christina , Zotter‐Tufaro Caroline , Koschutnik Matthias , Fiedler Lukas , Roithinger Franz Xaver , Loewe Christian , Hengstenberg Christian , Bonderman Diana , Mascherbauer Julia
Published: November 2019

Background

Atrial fibrillation (AF) is a frequent finding in HFpEF. However, its association with invasive haemodynamics, imaging parameters and outcome in HFpEF is not well established. Furthermore, the relevance of AF subtype with regard to outcome is unclear. This study sought to investigate the prognostic impact of paroxysmal and persistent AF in a well‐defined heart failure with preserved ejection fraction (HFpEF) population.

Materials and methods

Between 2010 and 2016, 254 HFpEF patients were prospectively enrolled. All patients underwent echocardiography as well as left and right heart catheterization. Patients without contraindications underwent CMR including T1 mapping. Follow‐up and outcome data were collected. Patients with significant coronary artery disease were excluded.

Results

A total of 153 patients (60%) suffered from AF, 119 (47%) had persistent and 34 (13%) had paroxysmal AF. By multiple logistic regression analysis, persistent AF was independently associated with NT‐proBNP (P = .003), NYHA functional class (P = .040), left and right atrial size (P = .022 and <.001, respectively), cardiac output (P = .002) and COPD (P = .034). After a median follow‐up of 23 months (interquartile range 5‐48), 92 patients (36%) reached the primary end point defined as hospitalization for heart failure or cardiovascular death. By multivariate Cox regression analysis, only persistent AF (P = .005) and six‐minute walk distance (P = .011) were independently associated with the primary end point.

Conclusions

Sixty percent of our HFpEF patients suffered from AF. Persistent but not paroxysmal AF was strongly associated with event‐free survival and was independently related to NYHA functional class, serum NT‐proBNP, atrial size, cardiac ouput and presence of COPD.