bluuebunny/crossref_metadata_2025_split huggingface dataset:
Refractory acute graft-versus-host disease: a new working definition beyond corticosteroid refractoriness
Authors: Mohty Mohamad , Holler Ernst , Jagasia Madan , Jenq Robert , Malard Florent , Martin Paul , Socié Gérard , Zeiser Robert 
Published: October 2020

Abstract
Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation. Only half of patients with severe acute GVHD respond to first-line treatment with corticosteroids and, for several decades, there was no optimal second-line treatment of patients with corticosteroid-refractory acute GVHD. Ruxolitinib was recently approved for the treatment of corticosteroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Thus, it is important to define the patient population that would now be considered as refractory to ruxolitinib vs ruxolitinib dependent. Here, we propose to define ruxolitinib-refractory acute GVHD as disease that shows: (1) progression of GVHD compared with baseline after at least 5 to 10 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement; (2) lack of improvement in GVHD (partial response or better) compared with baseline after ≥14 days of treatment with ruxolitinib; or (3) loss of response, defined as objective worsening of GVHD determined by increase in stage, grade, or new organ involvement at any time after initial improvement. GVHD manifestations that persist without improvement in patients who had a grade ≥3 treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib would serve as a clinical indication for additional treatment. In addition, absence of complete response or very good partial response at day 28 after ruxolitinib could be considered as an eligibility criterion.
Omics-based tracking ofPseudomonas aeruginosapersistence in “eradicated” cystic fibrosis patients
Authors: Bartell Jennifer A. , Sommer Lea M. , Marvig Rasmus L. , Skov Marianne , Pressler Tacjana , Molin Søren , Johansen Helle Krogh 
Published: October 2020

WheneverPseudomonas aeruginosais cultured from cystic fibrosis (CF) patient airways, the primary goal is eradication by antibiotic therapy. Success is defined by ≥6 months of negative bacterial airway cultures. However, we suspect thatP. aeruginosapersists in airways without clinical detection for long periods.Out of 298P. aeruginosa-infected Copenhagen CF patients, we identified 80 with completeP. aeruginosamonitoring records and measured their maximumP. aeruginosa-free eradication periods (MEP). Isolates from 72 patients were whole-genome sequenced (n=567) and clone typed. Select isolate relatedness was examined through phylogenetic analysis and phenotypic multivariate modelling.69 (86%) patients exhibited eradication in the monitoring period (2002–2018). Sequenced isolates bridged the MEP of 42 patients, and the same clone type persisted over the MEP in 18 (43%) patients. Patients with failed eradication were on average treated more intensively with antibiotics, but this may be linked to their more severe pre-MEP infection trajectories. Of the 42 patients, 26 also had sinus surgery; the majority (n=15) showed MEPs adjacent to surgery, and only five had persisting clone types. Importantly, combined phylogenetic–phenomic evaluation suggests that persisting clone types are a result of re-emergence of the same strain rather than re-infection from the environment, and similar relatedness is exhibited by paired lower and upper airway samples and in transmission cases.In conclusion, nearly half of CF patients with supposed eradication may not truly be cleared of their original bacteria according to omics-based monitoring. This distinct cohort that is persistently infected would probably benefit from tailored antibiotic therapy.
Real world effects of COPD medications: a cohort study with validation against results from randomised controlled trials
Authors: Wing Kevin , Williamson Elizabeth , Carpenter James R. , Wise Lesley , Schneeweiss Sebastian , Smeeth Liam , Quint Jennifer K. , Douglas Ian 
Published: October 2020

Real-world data provide the potential for generating evidence on drug treatment effects in groups excluded from trials, but rigorous, validated methodology for doing so is lacking. We investigated whether non-interventional methods applied to real-world data could reproduce results from the landmark TORCH COPD trial.We performed a historical cohort study (2000–2017) of COPD drug treatment effects in the UK Clinical Practice Research Datalink (CPRD). Two control groups were selected from CPRD by applying TORCH inclusion/exclusion criteria and 1:1 matching to TORCH participants, as follows. Control group 1: people with COPD not prescribed fluticasone propionate (FP)-salmeterol (SAL); control group 2: people with COPD prescribed SAL only. FP-SAL exposed groups were then selected from CPRD by propensity score matching to each control group. Outcomes studied were COPD exacerbations, death from any cause and pneumonia.2652 FP-SAL exposed people were propensity score matched to 2652 FP-SAL unexposed people while 991 FP-SAL exposed people were propensity score matched to 991 SAL exposed people. Exacerbation rate ratio was comparable to TORCH for FP-SALversusSAL (0.85, 95% CI 0.74–0.97versus0.88, 0.81–0.95) but not for FP-SALversusno FP-SAL (1.30, 1.19–1.42versus0.75, 0.69–0.81). In addition, active comparator results were consistent with TORCH for mortality (hazard ratio 0.93, 0.65–1.32versus0.93, 0.77–1.13) and pneumonia (risk ratio 1.39, 1.04–1.87versus1.47, 1.25–1.73).We obtained very similar results to the TORCH trial for active comparator analyses, but were unable to reproduce placebo-controlled results. Application of these validated methods for active comparator analyses to groups excluded from randomised controlled trials provides a practical way for contributing to the evidence base and supporting COPD treatment decisions.
A genome-wide association study of severe asthma exacerbations in Latino children and adolescents
Authors: Yan Qi , Forno Erick , Herrera-Luis Esther , Pino-Yanes Maria , Qi Cancan , Rios Raimon , Han Yueh-Ying , Kim Soyeon , Oh Sam , Acosta-Pérez Edna , Zhang Rong , Hu Donglei , Eng Celeste , Huntsman Scott , Avila Lydiana , Boutaoui Nadia , Cloutier Michelle M. , Soto-Quiros Manuel E. , Xu Cheng-Jian , Weiss Scott T. , Lasky-Su Jessica , Kiedrowski Megan R. , Figueiredo Camila , Bomberger Jennifer , Barreto Mauricio L. , Canino Glorisa , Chen Wei , Koppelman Gerard H. , Burchard Esteban G. , Celedón Juan C. 
Published: October 2020

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP inFLJ22447(rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34–1.79, p=6.3×10−9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at theFLJ22447locus, which was in turn associated with increased expression ofKCNJ2-AS1in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10−7).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG inFLJ22447and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1).
NCMHap: a novel method for haplotype reconstruction based on Neutrosophic c-means clustering
Authors: Zamani Fatemeh , Olyaee Mohammad Hossein , Khanteymoori Alireza 
Published: October 2020

AbstractBackgroundSingle individual haplotype problem refers to reconstructing haplotypes of an individual based on several input fragments sequenced from a specified chromosome. Solving this problem is an important task in computational biology and has many applications in the pharmaceutical industry, clinical decision-making, and genetic diseases. It is known that solving the problem is NP-hard. Although several methods have been proposed to solve the problem, it is found that most of them have low performances in dealing with noisy input fragments. Therefore, proposing a method which is accurate and scalable, is a challenging task.ResultsIn this paper, we introduced a method, named NCMHap, which utilizes the Neutrosophic c-means (NCM) clustering algorithm. The NCM algorithm can effectively detect the noise and outliers in the input data. In addition, it can reduce their effects in the clustering process. The proposed method has been evaluated by several benchmark datasets. Comparing with existing methods indicates when NCM is tuned by suitable parameters, the results are encouraging. In particular, when the amount of noise increases, it outperforms the comparing methods.ConclusionThe proposed method is validated using simulated and real datasets. The achieved results recommend the application of NCMHap on the datasets which involve the fragments with a huge amount of gaps and noise.
Positive selection in admixed populations from Ethiopia
Authors: Walsh Sandra , Pagani Luca , Xue Yali , Laayouni Hafid , Tyler-Smith Chris , Bertranpetit Jaume 
Published: October 2020

Abstract
Background
In the process of adaptation of humans to their environment, positive or adaptive selection has played a main role. Positive selection has, however, been under-studied in African populations, despite their diversity and importance for understanding human history.

Results
Here, we have used 119 available whole-genome sequences from five Ethiopian populations (Amhara, Oromo, Somali, Wolayta and Gumuz) to investigate the modes and targets of positive selection in this part of the world. The site frequency spectrum-based test SFselect was applied to idfentify a wide range of events of selection (old and recent), and the haplotype-based statistic integrated haplotype score to detect more recent events, in each case with evaluation of the significance of candidate signals by extensive simulations. Additional insights were provided by considering admixture proportions and functional categories of genes. We identified both individual loci that are likely targets of classic sweeps and groups of genes that may have experienced polygenic adaptation. We found population-specific as well as shared signals of selection, with folate metabolism and the related ultraviolet response and skin pigmentation standing out as a shared pathway, perhaps as a response to the high levels of ultraviolet irradiation, and in addition strong signals in genes such as IFNA, MRC1, immunoglobulins and T-cell receptors which contribute to defend against pathogens.

Conclusions
Signals of positive selection were detected in Ethiopian populations revealing novel adaptations in East Africa, and abundant targets for functional follow-up.
Studying polymorphic variants of the NAT2 gene (NAT2*5 and NAT2*7) in Nenets populations of Northern Siberia
Authors: Tiis Roza Pavlovna , Osipova Ludmila Pavlovna , Lichman Daria Veniaminovna , Voronina Elena Nikolaevna , Filipenko Maxim Leonidovich 
Published: October 2020

AbstractBackgroundN-acetyltransferase 2 plays a crucial role in the metabolism of a wide range of xenobiotics, including many drugs, carcinogens, and other chemicals in the human environment. The article presents for the first time data on the frequency of two important “slow” variants ofNAT2gene(NAT2*5, rs1801280 andNAT2*7, rs1799931),which significantly affect the rate of xenobiotics acetylation, among representatives of indigenous populations of Forest and Tundra Nenets in Northern Siberia. The aim of this study was to identify the frequencies of these variants and compare them with frequencies in other ethnic populations.ResultsNAT2*5(T341C) genotyping revealed frequencies of 28,0% and 38,6% for Tundra and Forest Nenets, respectively. The frequencies ofNAT2*7(G857A) variant were 9,8% and 8,2% for Tundra and Forest Nenets, respectively. Polymorphic variants frequencies for Nenets are intermediate between those in populations of Europeans and Asians. These results can probably be explained by the presence of both European and Asian components in Nenets gene pools.ConclusionsThe results of this study expand the knowledge ofNAT2polymorphism in world populations. These data may also help assess the genetic predisposition of Nenets to multifactorial diseases associated with polymorphism in theNAT2gene and, in general, contribute to the development of personalized medicine in reference to native people of Siberia.
Genome-wide identification and functional analysis of the TIFY gene family in the response to multiple stresses in Brassica napus L.
Authors: He Xin , Kang Yu , Li Wenqian , Liu Wei , Xie Pan , Liao Li , Huang Luyao , Yao Min , Qian Lunwen , Liu Zhongsong , Guan Chunyun , Guan Mei , Hua Wei 
Published: October 2020

Abstract
Background
TIFY is a plant-specific protein family with a diversity of functions in plant development and responses to stress and hormones, which contains JASMONATE ZIM-domain (JAZ), TIFY, PPD and ZML subfamilies. Despite extensive studies of TIFY family in many other species, TIFY has not yet been characterized in Brassica napus.

Results
In this study, we identified 77, 36 and 39 TIFY family genes in the genome of B. napus, B. rapa and B. oleracea, respectively. Results of the phylogenetic analysis indicated the 170 TIFY proteins from Arabidopsis, B. napus, B. rapa and B. oleracea could be divided into 11 groups: seven JAZ groups, one PPD group, one TIFY group, and two ZIM/ZML groups. The molecular evolutionary analysis showed that TIFY genes were conserved in Brassicaceae species. Gene expression profiling and qRT-PCR revealed that different groups of BnaTIFY members have distinct spatiotemporal expression patterns in normal conditions or following treatment with different abiotic/biotic stresses and hormones. The BnaJAZ subfamily genes were predominantly expressed in roots and up-regulated by NaCl, PEG, freezing, methyl jasmonate (MeJA), salicylic acid (SA) and Sclerotinia sclerotiorum in leaves, suggesting that they have a vital role in hormone signaling to regulate multiple stress tolerance in B. napus.

Conclusions
The extensive annotation and expression analysis of the BnaTIFY genes contributes to our understanding of the functions of these genes in multiple stress responses and phytohormone crosstalk in B. napus.
Genome-wide study of pineapple (Ananas comosus L.) bHLH transcription factors indicates that cryptochrome-interacting bHLH2 (AcCIB2) participates in flowering time regulation and abiotic stress response
Authors: Aslam Mohammad , Jakada Bello Hassan , Fakher Beenish , Greaves Joseph G. , Niu Xiaoping , Su Zhenxia , Cheng Yan , Cao Shijiang , Wang Xiaomei , Qin Yuan 
Published: October 2020

Abstract
Background
Transcription factors (TFs) are essential regulators of growth and development in eukaryotes. Basic-helix-loop-helix (bHLHs) is one of the most significant TFs families involved in several critical regulatory functions. Cryptochrome-interacting bHLH (CIB) and cryptochromes form an extensive regulatory network to mediate a plethora of pathways. Although bHLHs regulate critical biological processes in plants, the information about pineapple bHLHs remains unexplored.

Results
Here, we identified a total of 121 bHLH proteins in the pineapple genome. The identified genes were renamed based on the ascending order of their gene ID and classified into 18 subgroups by phylogenetic analysis. We found that bHLH genes are expressed in different organs and stages of pineapple development. Furthermore, by the ectopic expression of AcCIB2 in Arabidopsis and complementation of Atcib2 mutant, we verified the involvement of AcCIB2 in photomorphogenesis and abiotic stress response.

Conclusions
Our findings revealed that AcCIB2 plays an essential role in flowering time regulation and abiotic stress response. The present study provides additional insights into the current knowledge of bHLH genes and suggests their potential role in various biological processes during pineapple development.
Variation in the expression of a transmembrane protein influences cell growth in Arabidopsis thaliana petals by altering auxin responses
Authors: Miller Charlotte N. , Dumenil Jack , Lu Fu Hao , Smith Caroline , McKenzie Neil , Chapman Volodymyr , Ball Joshua , Box Mathew , Bevan Michael 
Published: October 2020

Abstract
Background
The same species of plant can exhibit very diverse sizes and shapes of organs that are genetically determined. Characterising genetic variation underlying this morphological diversity is an important objective in evolutionary studies and it also helps identify the functions of genes influencing plant growth and development. Extensive screens of mutagenised Arabidopsis populations have identified multiple genes and mechanisms affecting organ size and shape, but relatively few studies have exploited the rich diversity of natural populations to identify genes involved in growth control.

Results
We screened a relatively well characterised collection of Arabidopsis thaliana accessions for variation in petal size. Association analyses identified sequence and gene expression variation on chromosome 4 that made a substantial contribution to differences in petal area. Variation in the expression of a previously uncharacterised gene At4g16850 (named as KSK) had a substantial role on variation in organ size by influencing cell size. Over-expression of KSK led to larger petals with larger cells and promoted the formation of stamenoid features. The expression of auxin-responsive genes known to limit cell growth was reduced in response to KSK over-expression. ANT expression was also reduced in KSK over-expression lines, consistent with altered floral identities. Auxin responses were reduced in KSK over-expressing cells, consistent with changes in auxin-responsive gene expression. KSK may therefore influence auxin responses during petal development.

Conclusions
Understanding how genetic variation influences plant growth is important for both evolutionary and mechanistic studies. We used natural populations of Arabidopsis thaliana to identify sequence variation in a promoter region of Arabidopsis accessions that mediated differences in the expression of a previously uncharacterised membrane protein. This variation contributed to altered auxin responses and cell size during petal growth.
Molecular insights into the compatible and incompatible interactions between sugar beet and the beet cyst nematode
Authors: Ghaemi Razieh , Pourjam Ebrahim , Safaie Naser , Verstraeten Bruno , Mahmoudi Seyed Bagher , Mehrabi Rahim , De Meyer Tim , Kyndt Tina 
Published: October 2020

Abstract
Background
Sugar beet (Beta vulgaris subsp. vulgaris) is an economically important crop that provides nearly one third of the global sugar production. The beet cyst nematode (BCN), Heterodera schachtii, causes major yield losses in sugar beet and other crops worldwide. The most effective and economic approach to control this nematode is growing tolerant or resistant cultivars. To identify candidate genes involved in susceptibility and resistance, the transcriptome of sugar beet and BCN in compatible and incompatible interactions at two time points was studied using mRNA-seq.

Results
In the susceptible cultivar, most defense-related genes were induced at 4 dai while suppressed at 10 dai but in the resistant cultivar Nemakill, induction of genes involved in the plant defense response was observed at both time points. In the compatible interaction, alterations in phytohormone-related genes were detected. The effect of exogenous application of Methyl Jasmonate and ET-generator ethephon on susceptible plants was therefore investigated and the results revealed significant reduction in plant susceptibility. Genes putatively involved in the resistance of Nemakill were identified, such as genes involved in phenylpropanoid pathway and genes encoding CYSTM domain-containing proteins, F-box proteins, chitinase, galactono-1,4-lactone dehydrogenase and CASP-like protein. Also, the transcriptome of the BCN was analyzed in infected root samples and several novel potential nematode effector genes were found.

Conclusions
Our data provides detailed insights into the plant and nematode transcriptional changes occurring during compatible and incompatible interactions between sugar beet and BCN. Many important genes playing potential roles in susceptibility or resistance of sugar beet against BCN, as well as some BCN effectors with a potential role as avr proteins were identified. In addition, our findings indicate the effective role of jasmonate and ethylene in enhancing sugar beet defense response against BCN. This research provides new molecular insights into the plant-nematode interactions that can be used to design novel management strategies against BCN.
Estimation in meta-analyses of response ratios
Authors: Bakbergenuly Ilyas , Hoaglin David C. , Kulinskaya Elena 
Published: October 2020

Abstract
Background
For outcomes that studies report as the means in the treatment and control groups, some medical applications and nearly half of meta-analyses in ecology express the effect as the ratio of means (RoM), also called the response ratio (RR), analyzed in the logarithmic scale as the log-response-ratio, LRR.

Methods
In random-effects meta-analysis of LRR, with normal and lognormal data, we studied the performance of estimators of the between-study variance, τ2, (measured by bias and coverage) in assessing heterogeneity of study-level effects, and also the performance of related estimators of the overall effect in the log scale, λ. We obtained additional empirical evidence from two examples.

Results
The results of our extensive simulations showed several challenges in using LRR as an effect measure. Point estimators of τ2 had considerable bias or were unreliable, and interval estimators of τ2 seldom had the intended 95% coverage for small to moderate-sized samples (n<40). Results for estimating λ differed between lognormal and normal data.

Conclusions
For lognormal data, we can recommend only SSW, a weighted average in which a study’s weight is proportional to its effective sample size, (when n≥40) and its companion interval (when n≥10). Normal data posed greater challenges. When the means were far enough from 0 (more than one standard deviation, 4 in our simulations), SSW was practically unbiased, and its companion interval was the only option.