bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silicoprediction and characterisation of secondary metabolite clusters in the plant pathogenic fungusVerticillium dahliae
Authors: Shi-Kunne Xiaoqian , Jové Roger de Pedro , Depotter Jasper R L , Ebert Malaika K , Seidl Michael F , Thomma Bart P H J 
Published: April 2019

ABSTRACTFungi are renowned producers of natural compounds, also known as secondary metabolites (SMs) that display a wide array of biological activities. Typically, the genes that are involved in the biosynthesis of SMs are located in close proximity to each other in so-called secondary metabolite clusters. Many plant-pathogenic fungi secrete SMs during infection in order to promote disease establishment, for instance as cytocoxic compounds. Verticillium dahliae is a notorious plant pathogen that can infect over 200 host plants worldwide. However, the SM repertoire of this vascular pathogen remains mostly uncharted. To unravel the potential of V. dahliae to produce SMs, we performed in silico predictions and in-depth analyses of its secondary metabolite clusters. Using distinctive traits of gene clusters and the conserved signatures of core genes 25 potential SM gene clusters were identified. Subsequently, phylogenetic and comparative genomics analyses were performed, revealing that two putative siderophores, ferricrocin and TAFC, DHN-melanin and fujikurin may belong to the SM repertoire of V. dahliae.
A cost-effectiveness analysis of maternal and neonatal health interventions in Ethiopia
Authors: Memirie Solomon Tessema , Tolla Mieraf Taddesse , Desalegn Dawit , Hailemariam Mengistu , Norheim Ole Frithjof , Verguet Stéphane , Johansson Kjell Arne 
Published: April 2019

Abstract
Ethiopia is one of the sub-Saharan African countries contributing to the highest number of maternal and neonatal deaths. Coverage of maternal and neonatal health (MNH) interventions has remained very low in Ethiopia. We examined the cost-effectiveness of selected MNH interventions in an Ethiopian setting. We analysed 13 case management and preventive MNH interventions. For all interventions, we used an ingredients-based approach for cost estimation. We employed a static life table model to estimate the health impact of a 20% increase in intervention coverage relative to the baseline. We used disability-adjusted life years (DALYs) as the health outcome measure while costs were expressed in 2018 US$. Analyses were based on local epidemiological, demographic and cost data when available. Our finding shows that 12 out of the 13 interventions included in our analysis were highly cost-effective. Interventions targeting newborns such as neonatal resuscitation (institutional), kangaroo mother care and management of newborn sepsis with injectable antibiotics were the most cost-effective interventions with incremental cost-effectiveness ratios of US$7, US$8 and US$17 per DALY averted, respectively. Obstetric interventions (induction of labour, active management of third stage of labour, management of pre-eclampsia/eclampsia and maternal sepsis, syphilis treatment and tetanus toxoid during pregnancy) and safe abortion cost between US$100 and US$300 per DALY averted. Calcium supplementation for pre-eclampsia and eclampsia prevention was the least cost-effective, with a cost per DALY of about US$3100. Many of the MNH interventions analysed were highly cost-effective, and this evidence can inform the ongoing essential health services package revision in Ethiopia. Our analysis also shows that calcium supplementation does not appear to be cost-effective in our setting.
The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson’s disease
Authors: Yi Wei , MacDougall Emma J , Tang Matthew Y , Krahn Andrea I , Gan-Or Ziv , Trempe Jean-François , Fon Edward A 
Published: April 2019

Abstract
Mutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early-onset Parkinson’s disease (EOPD). Hundreds of naturally occurring Parkin variants have been reported, both in Parkinson's disease (PD) patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remain unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence—including measures of mitophagy and protein stability and predictive structural modeling—and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.
Precise genome editing using a CRISPR-Cas9 method highlights the role of CoERG11 amino acid substitutions in azole resistance in Candida orthopsilosis
Authors: Morio Florent , Lombardi Lisa , Binder Ulrike , Loge Cédric , Robert Estelle , Graessle Denise , Bodin Marine , Lass-Flörl Cornelia , Butler Geraldine , Le Pape Patrice 
Published: April 2019

AbstractBackgroundAzoles are one of the main antifungal classes for the treatment of candidiasis. In the current context of emerging drug resistance, most studies have focused on Candida albicans, Candida glabrata or Candida auris but, so far, less is known about the underlying mechanisms of resistance in other species, including Candida orthopsilosis.ObjectivesWe investigated azole resistance in a C. orthopsilosis clinical isolate recovered from a patient with haematological malignancy receiving fluconazole prophylaxis.MethodsAntifungal susceptibility to fluconazole was determined in vitro (CLSI M27-A3) and in vivo (in a Galleria mellonella model of invasive candidiasis). The CoERG11 gene was then sequenced and amino acid substitutions identified were mapped on the predicted 3D structure of CoErg11p. A clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) genome-editing strategy was used to introduce relevant mutations into a fluconazole-susceptible C. orthopsilosis isolate.ResultsCompared with unrelated C. orthopsilosis isolates, the clinical isolate exhibited both in vitro and in vivo fluconazole resistance. Sequencing of the CoERG11 gene identified several amino acid substitutions, including two possibly involved in fluconazole resistance (L376I and G458S). Both mutations mapped close to the active site of CoErg11p. Engineering these mutations in a different genetic background using CRISPR-Cas9 demonstrated that G458S, but not L376I, confers resistance to fluconazole and voriconazole.ConclusionsOur data show that the G458S amino acid substitution in CoERG11p, but not L376I, contributes to azole resistance in C. orthopsilosis. In addition to highlighting the potential of CRISPR-Cas9 technology for precise genome editing in the field of antifungal resistance, we discuss some points that are critical to improving its efficiency.
Research-grade data in the real world: challenges and opportunities in data quality from a pragmatic trial in community-based practices
Authors: Divney Anna A , Lopez Priscilla M , Huang Terry T , Thorpe Lorna E , Trinh-Shevrin Chau , Islam Nadia S 
Published: April 2019

Abstract
Randomized controlled trials face cost, logistic, and generalizability limitations, including difficulty engaging racial/ethnic minorities. Real-world data (RWD) from pragmatic trials, including electronic health record (EHR) data, may produce intervention evaluation findings generalizable to diverse populations. This case study of Project IMPACT describes unique barriers and facilitators of optimizing RWD to improve health outcomes and advance health equity in small immigrant-serving community-based practices. Project IMPACT tested the effect of an EHR-based health information technology intervention on hypertension control among small urban practices serving South Asian patients. Challenges in acquiring accurate RWD included EHR field availability and registry capabilities, cross-sector communication, and financial, personnel, and space resources. Although using RWD from community-based practices can inform health equity initiatives, it requires multidisciplinary collaborations, clinic support, procedures for data input (including social determinants), and standardized field logic/rules across EHR platforms.
The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer
Authors: Watanabe Hiromi , Kubo Toshio , Ninomiya Kiichiro , Kudo Kenichiro , Minami Daisuke , Murakami Etsuko , Ochi Nobuaki , Ninomiya Takashi , Harada Daijiro , Yasugi Masayuki , Ichihara Eiki , Ohashi Kadoaki , Fujiwara Keiichi , Hotta Katsuyuki , Tabata Masahiro , Maeda Yoshinobu , Kiura Katsuyuki 
Published: April 2019

Abstract

Introduction
Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients.

Methods
We defined ‘rechallenge’ as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers.

Results
A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8–2.6] and 6.5 months [95% CI: 1.4–19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs.

Conclusions
In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.
Elevating H3K27me3 level sensitizes colorectal cancer to oxaliplatin
Authors: Wang Qi , Chen Xi , Jiang Yuhang , Liu Sanhong , Liu Hanshao , Sun Xiaohua , Zhang Haohao , Liu Zhi , Tao Yu , Li Cuifeng , Hu Yiming , Liu Dandan , Ye Deji , Liu Yongzhong , Wang Mingliang , Zhang Xiaoren 
Published: April 2019

AbstractHistone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.
The effects of 50 Hz magnetic field–exposed cell culture medium on cellular functions in FL cells
Authors: Fei Yue , Su Liling , Lou Haifeng , Zhao Chuning , Wang Yiqin , Chen Guangdi 
Published: April 2019

Abstract
Although extremely low frequency magnetic fields (ELF-MFs) have been classified as a possible carcinogen for humans by the International Agency for Research on Cancer (IARC), their biological effects and underlying mechanisms are still unclear. Our previous study indicated that ELF-MF exposure influenced the relative permittivity of the saline solution, suggesting that the MF exposure altered physical properties of the solution. To explore the biophysical mechanism of ELF-MF–induced biological effects, this study examined the effects of 50 Hz sinusoidal MF at 0–4.0 mT on the permittivity of culture medium with phase-interrogation surface plasmon resonance (SPR) sensing. Then, the biological effects of MF pre-exposed culture medium on cell viability, the mitogen-activated protein kinase (MAPK) signaling pathways, oxidative stress, and genetic stabilities were analyzed using Cell Counting Kit-8, western blot, flow cytometry, γH2AX foci formation, and comet assay. The results showed that SPR signals were decreased under MF exposure in a time- and dose-dependent manner, and the decreased SPR signals were reversible when the exposure was drawn off. However, MF pre-exposed culture medium did not significantly change cell viability, intracellular reactive oxygen species level, activation of the MARK signaling pathways, or genetic stabilities in human amniotic epithelial cells (FL cells). In conclusion, our data suggest that the relative permittivity of culture medium was influenced by 50 Hz MF exposure, but this change did not affect the biological processes in FL cells.
PhyloToL: A Taxon/Gene-Rich Phylogenomic Pipeline to Explore Genome Evolution of Diverse Eukaryotes
Authors: Cerón-Romero Mario A , Maurer-Alcalá Xyrus X , Grattepanche Jean-David , Yan Ying , Fonseca Miguel M , Katz L A 
Published: April 2019

Abstract
Estimating multiple sequence alignments (MSAs) and inferring phylogenies are essential for many aspects of comparative biology. Yet, many bioinformatics tools for such analyses have focused on specific clades, with greatest attention paid to plants, animals, and fungi. The rapid increase in high-throughput sequencing (HTS) data from diverse lineages now provides opportunities to estimate evolutionary relationships and gene family evolution across the eukaryotic tree of life. At the same time, these types of data are known to be error-prone (e.g., substitutions, contamination). To address these opportunities and challenges, we have refined a phylogenomic pipeline, now named PhyloToL, to allow easy incorporation of data from HTS studies, to automate production of both MSAs and gene trees, and to identify and remove contaminants. PhyloToL is designed for phylogenomic analyses of diverse lineages across the tree of life (i.e., at scales of >100 My). We demonstrate the power of PhyloToL by assessing stop codon usage in Ciliophora, identifying contamination in a taxon- and gene-rich database and exploring the evolutionary history of chromosomes in the kinetoplastid parasite Trypanosoma brucei, the causative agent of African sleeping sickness. Benchmarking PhyloToL’s homology assessment against that of OrthoMCL and a published paper on superfamilies of bacterial and eukaryotic organellar outer membrane pore-forming proteins demonstrates the power of our approach for determining gene family membership and inferring gene trees. PhyloToL is highly flexible and allows users to easily explore HTS data, test hypotheses about phylogeny and gene family evolution and combine outputs with third-party tools (e.g., PhyloChromoMap, iGTP).
Responsive self-assembly of tectoRNAs with loop–receptor interactions from the tetrahydrofolate (THF) riboswitch
Authors: Mitchell Charles , Polanco Julio A , DeWald Laura , Kress Dustin , Jaeger Luc , Grabow Wade W 
Published: April 2019

Abstract
Naturally occurring RNAs are known to exhibit a high degree of modularity, whereby specific structural modules (or motifs) can be mixed and matched to create new molecular architectures. The modular nature of RNA also affords researchers the ability to characterize individual structural elements in controlled synthetic contexts in order to gain new and critical insights into their particular structural features and overall performance. Here, we characterized the binding affinity of a unique loop–receptor interaction found in the tetrahydrofolate (THF) riboswitch using rationally designed self-assembling tectoRNAs. Our work suggests that the THF loop–receptor interaction has been fine-tuned for its particular role as a riboswitch component. We also demonstrate that the thermodynamic stability of this interaction can be modulated by the presence of folinic acid, which induces a local structural change at the level of the loop–receptor. This corroborates the existence of a THF binding site within this tertiary module and paves the way for its potential use as a THF responsive module for RNA nanotechnology and synthetic biology.
MRPrimerW2: an enhanced tool for rapid design of valid high-quality primers with multiple search modes for qPCR experiments
Authors: Jeon Hajin , Bae Jeongmin , Hwang Sang-Hyun , Whang Kyu-Young , Lee Hyun-Seob , Kim Hyerin , Kim Min-Soo 
Published: April 2019

Abstract
For the best results in quantitative polymerase chain reaction (qPCR) experiments, it is essential to design high-quality primers considering a multitude of constraints and the purpose of experiments. The constraints include many filtering constraints, homology test on a huge number of off-target sequences, the same constraints for batch design of primers, exon spanning, and avoiding single nucleotide polymorphism (SNP) sites. The target sequences are either in database or given as FASTA sequences, and the experiment is for amplifying either each target sequence with each corresponding primer pairs designed under the same constraints or all target sequences with a single pair of primers. Many websites have been proposed, but none of them including our previous MRPrimerW fulfilled all the above features. Here, we describe the MRPrimerW2, the update version of MRPrimerW, which fulfils all the features by maintaining the advantages of MRPrimerW in terms of the kinds and sizes of databases for valid primers and the number of search modes. To achieve it, we exploited GPU computation and a disk-based key-value store using PCIe SSD. The complete set of 3 509 244 680 valid primers of MRPrimerW2 covers 99% of nine important organisms in an exhaustive manner. Free access: http://MRPrimerW2.com
Reporting Methodology of Neurosurgical Studies Utilizing the American College of Surgeons-National Surgical Quality Improvement Program Database: A Systematic Review and Critical Appraisal
Authors: Yolcu Yagiz , Wahood Waseem , Alvi Mohammed Ali , Kerezoudis Panagiotis , Habermann Elizabeth B , Bydon Mohamad 
Published: April 2019

Abstract

BACKGROUND
Use of large databases such as the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) has become increasingly common in neurosurgical research.

OBJECTIVE
To perform a critical appraisal and evaluation of the methodological reporting for studies in neurosurgical literature that utilize the ACS-NSQIP database.

METHODS
We queried Ovid MEDLINE, EMBASE, and PubMed databases for all neurosurgical studies utilizing the ACS-NSQIP. We assessed each study according to number of criteria fulfilled with respect to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement, REporting of studies Conducted using Observational Routinely-collected Health Data (RECORD) Statement, and Journal of American Medical Association–Surgical Section (JAMA-Surgery) Checklist. A separate analysis was conducted among papers published in core and noncore journals in neurosurgery according to Bradford's law.

RESULTS
A total of 117 studies were included. Median (interquartile range [IQR]) scores for number of fulfilled criteria for STROBE Statement, RECORD Statement, and JAMA-Surgery Checklist were 20 (IQR:19-21), 9 (IQR:8-9), and 6 (IQR:5-6), respectively. For STROBE Statement, RECORD Statement, and JAMA-Surgery Checklist, item 9 (potential sources of bias), item 13 (supplemental information), and item 9 (missing data/sensitivity analysis) had the highest number of studies with no fulfillment among all studies (56, 68, 50%), respectively. When comparing core journals vs noncore journals, no significant difference was found (STROBE, P = .94; RECORD, P = .24; JAMA-Surgery checklist, P = .60).

CONCLUSION
While we observed an overall satisfactory reporting of methodology, most studies lacked mention of potential sources of bias, data cleaning methods, supplemental information, and external validity. Given the pervasive role of national databases and registries for research and health care policy, the surgical community needs to ensure the credibility and quality of such studies that ultimately aim to improve the value of surgical care delivery to patients.
Identifying areas for improvement in paediatric inpatient care using the Child HCAHPS survey
Authors: Ahmed Sadia , Kemp Kyle , Johnson David , Quan Hude , Santana Maria Jose 
Published: April 2019

Abstract

The Child-Hospital Consumer Assessment of Healthcare Providers and Systems (Child-HCAHPS) survey is a validated measure of paediatric inpatient experience. The study objective was to determine which survey questions were most correlated with respondents’ overall rating of care. Knowing which questions are most important may provide valuable insights for developing targeted quality improvement initiatives.

Methods
Within 6 weeks of discharge, 3,389 telephone surveys were completed by parents/guardians of children who were hospitalized for at least 24 hours. The survey was comprised of 66 questions, with responses based on Likert-scales. One survey question asked respondents to rate the overall care that their child received on a scale from 0 (worst care) to 10 (best care). The correlation between the overall rating of care and each survey measure and question was then examined using Spearman correlation coefficients. All survey questions were normalized to a 100-point score (0=worst, 100=best).

Results
Questions on provider coordination and nursing care were most correlated with overall experience. Quietness of hospital room (r=0.19, P&lt;0.001), and keeping families informed in the emergency room (r=0.12, P&lt;0.001) showed poor correlation. Correlation with overall experience was strongest for the ‘communication with nurses’ domain (r=0.46, P&lt;0.001).

Conclusions
To our knowledge, this is the first study which examines the correlation of individual questions of the Child-HCAHPS to overall rating of care within a Canadian context. Our results suggest that our large health care organization may attain initial inpatient experience improvements by focusing upon personnel-based initiatives, rather than physical attributes of our hospitals.