bluuebunny/crossref_metadata_2025_split huggingface dataset:
A clustering linear combination approach to jointly analyze multiple phenotypes for GWAS
Authors: Sha Qiuying , Wang Zhenchuan , Zhang Xiao , Zhang Shuanglin 
Published: September 2018

Abstract

Summary
There is an increasing interest in joint analysis of multiple phenotypes for genome-wide association studies (GWASs) based on the following reasons. First, cohorts usually collect multiple phenotypes and complex diseases are usually measured by multiple correlated intermediate phenotypes. Second, jointly analyzing multiple phenotypes may increase statistical power for detecting genetic variants associated with complex diseases. Third, there is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. In this paper, we develop a clustering linear combination (CLC) method to jointly analyze multiple phenotypes for GWASs. In the CLC method, we first cluster individual statistics into positively correlated clusters and then, combine the individual statistics linearly within each cluster and combine the between-cluster terms in a quadratic form. CLC is not only robust to different signs of the means of individual statistics, but also reduce the degrees of freedom of the test statistic. We also theoretically prove that if we can cluster the individual statistics correctly, CLC is the most powerful test among all tests with certain quadratic forms. Our simulation results show that CLC is either the most powerful test or has similar power to the most powerful test among the tests we compared, and CLC is much more powerful than other tests when effect sizes align with inferred clusters. We also evaluate the performance of CLC through a real case study.

Availability and implementation
R code for implementing our method is available at http://www.math.mtu.edu/∼shuzhang/software.html.

Supplementary information
Supplementary data are available at Bioinformatics online.
Gimpute: an efficient genetic data imputation pipeline
Authors: Chen Junfang , Lippold Dietmar , Frank Josef , Rayner William , Meyer-Lindenberg Andreas , Schwarz Emanuel 
Published: September 2018

AbstractMotivationGenotype imputation is essential for genome-wide association studies (GWAS) to retrieve information of untyped variants and facilitate comparability across studies. However, there is a lack of automated pipelines that perform all required processing steps prior to and following imputation.ResultsBased on widely used and freely available tools, we have developed Gimpute, an automated processing and imputation pipeline for genome-wide association data. Gimpute includes processing steps for genotype liftOver, quality control, population outlier detection, haplotype pre-phasing, imputation, post imputation, data management and the extension to other existing pipeline.Availability and implementationThe Gimpute package is an open source R package and is freely available at https://github.com/transbioZI/Gimpute.Supplementary informationSupplementary data are available at Bioinformatics online.
RNApuzzler: efficient outerplanar drawing of RNA-secondary structures
Authors: Wiegreffe Daniel , Alexander Daniel , Stadler Peter F , Zeckzer Dirk 
Published: September 2018

Abstract

Motivation
RNA secondary structure is a useful representation for studying the function of RNA, which captures most of the free energy of RNA folding. Using empirically determined energy parameters, secondary structures of nucleic acids can be efficiently computed by recursive algorithms. Several software packages supporting this task are readily available. As RNA secondary structures are outerplanar graphs, they can be drawn without intersection in the plane. Interpretation by the practitioner is eased when these drawings conform to a series of additional constraints beyond outerplanarity. These constraints are the reason why RNA drawing is difficult. Many RNA drawing algorithms therefore do not always produce intersection-free (outerplanar) drawings.

Results
To remedy this shortcoming we propose here the RNApuzzler algorithm which is guaranteed to produce intersection-free drawings. It is based on a drawing algorithm respecting constraints based on nucleotide distances (RNAturtle). We investigate relaxations of these constraints allowing for intersection-free drawings. Based on these relaxations, we implemented a fully automated, simple, and robust algorithm that produces aesthetic drawings adhering to previously established guidelines. We tested our algorithm using the RFAM database and found that we can compute intersection-free drawings of all RNAs therein efficiently.

Availability and implementation
The software can be accessed freely at: https://github.com/dwiegreffe/RNApuzzler.

Supplementary information
Supplementary data are available at Bioinformatics online.
Quantitative solid-phase assay to measure deoxynucleoside triphosphate pools
Authors: Landoni Juan Cruz , Wang Liya , Suomalainen Anu 
Published: September 2018

Abstractdeoxynucleoside triphosphate (dNTPs) are the reduced nucleotides used as the building blocks and energy source for deoxyribonucleic acid (DNA) replication and maintenance in all living systems. They are present in highly regulated amounts and ratios in the cell, and their balance has been implicated in the most important cell processes, from determining the fidelity of DNA replication to affecting cell fate. Furthermore, many cancer drugs target biosynthetic enzymes in dNTP metabolism, and mutations in genes directly or indirectly affecting these pathways that are the cause of devastating diseases. The accurate and systematic measurement of these pools is key to understanding the mechanisms behind these diseases and their treatment. We present a new method for measuring dNTP pools from biological samples, utilizing the current state-of-the-art polymerase method, modified to a solid-phase setting and optimized for larger scale measurements.
Towards the third 90: improving viral load testing with a simple quality improvement program in health facilities in Malawi
Authors: Hubbard Julie , Kakwesa Gift , Nyirenda Mike , Mwambene James , Bardon Ashley , Balakasi Kelvin , Dovel Kathryn , Kalua Thokozani , Hoffman Risa M 
Published: September 2018

AbstractBackgroundViral load (VL) scale-up efforts have largely focused on laboratory systems, with less attention on facility-level strengthening of staff who facilitate VL testing. To address this gap we implemented a quality improvement (QI) program at 13 health facilities in central and southern Malawi.MethodsQI program tools focused on patient and provider VL knowledge and clarification of site-level roles and responsibilities, including the designation of a VL ‘focal person’ to oversee all VL activities. T-tests were used to compare differences in VL testing before (November 2016–April 2017) and after (May 2017–November 2017) the intervention.ResultsThe mean number of VL tests performed significantly increased after implementation of the QI program. Overall there was a 164% increase in the mean number of routine VL tests performed per month (p&lt;0.001). Increased VL testing was sustained during the 6 months of follow-up.ConclusionsA simple QI program focused on improving VL knowledge among patients and providers, and clarifying staff roles at a facility level increased VL testing over a 6-month period. Further investigation is needed on whether this program can be scaled in different settings across sub-Saharan Africa and on the duration of follow-up required for sustained improvements in VL testing.
Monopoiesis in humans and mice
Authors: Kawamura Shunsuke , Ohteki Toshiaki 
Published: September 2018

AbstractMonocytes are a widely conserved cell population in vertebrates with important roles in both inflammation and homeostasis. Under both settings, monocytes continuously arise from hematopoietic progenitors in the bone marrow and, on demand, migrate into tissues through the bloodstream. Monocytes are classified into three subsets—classical, intermediate and non-classical—based on their cell surface expression of CD14 and CD16 in humans and Ly6C, CX3CR1 and CCR2 in mice. In tissues, monocytes differentiate further into monocyte-derived macrophages and dendritic cells to mediate innate and adaptive immune responses and maintain tissue homeostasis. Recently, the progenitors that strictly give rise to monocytes were identified in both humans and mice, thereby revealing the monocyte differentiation pathways.
Reliability and validity of the Thai Drug Hypersensitivity Quality of Life Questionnaire: a multi-center study
Authors: Chongpison Yuda , Rerknimitr Pawinee , Hurst Cameron , Mongkolpathumrat Pungjai , Palapinyo Sirinoot , Chularojanamontri Leena , Srinoulprasert Yuttana , Rerkpattanapipat Ticha , Chanprapaph Kumutnart , Disphanurat Wareeporn , Chakkavittumrong Panlop , Tovanabutra Napatra , Srisuttiyakorn Chutika , Sukasem Chonlaphat , Tuchinda Papapit , Baiardini Ilaria , Klaewsongkram Jettanong 
Published: September 2018

AbstractObjectiveTo adapted the Drug Hypersensitivity Quality of Life (DrHy-Q) Questionnaire from Italian into Thai and assessed its validity and reliability.DesignProspectively recruited during January 2012–May 2017.SettingMulticenter; six Thai tertiary university hospitals.Study ParticipantsTotal of 306 patients with physician-diagnosed drug hypersensitivity.InterventionsInternal consistency and test–retest reliability were evaluated among 68 participants using Cronbach’s ɑ and intra-class correlation coefficient (ICC). The validity of Thai DrHy-Q was assessed among 306 participants who completed World Health Organization Quality of Life-BREF (WHOQOL-BREF-THAI). Construct and divergent validities were assessed for Thai DrHy-Q. Known-groups validity assessing discriminating ability was conducted in Thai DrHy-Q and WHOQOL-BREF-THAI.Main outcome measuresValidity; reliability; single vs. multiple drug allergy; non-severe cutaneous adverse reactions (SCAR) vs. SCAR.ResultsThai DrHy-Q showed good reliability (Cronbach’s ɑ = 0.94 and ICC = 0.8). Unidimensional factor structure was established by confirmatory factor analysis (CFI&TLI = 0.999, RMSEA = 0.02). Divergent validity was confirmed by weak correlation between Thai DrHy-Q and WHOQOL-BREF-THAI domains (Pearson’s r = −0.41 to −0.19). Known-groups validity of Thai DrHy-Q was confirmed with significant difference between patients with and without life-threatening SCAR (P = 0.02) and patients with multiple implicated drug classes vs. those with one class (P < 0.01); while WHOQOL-BREF-THAI could differentiate presence of life-threatening SCAR (P < 0.01) but not multiple-drug allergy.ConclusionsThai DrHy-Q was reliable and valid in evaluating quality of life among patients with drug hypersensitivity. Thai DrHy-Q was able to discriminate serious drug allergy phenotypes from non-serious manifestations in clinical practice and capture more specific drug-hypersensitivity aspects than WHOQOL-BREF-THAI.
Separation and Identification of Isomeric and Structurally Related Synthetic Cannabinoids Using 2D Liquid Chromatography and High Resolution Mass Spectrometry
Authors: Eckberg Melanie N , Arroyo-Mora Luis E , Stoll Dwight R , DeCaprio Anthony P 
Published: September 2018

Abstract
Novel psychoactive substances (NPS) are emerging drugs of abuse that are variations of existing compounds intended to cause a CNS psychotropic effect. Some NPS are so comparable in structure and physicochemical properties that they co-elute using traditional single column chromatographic techniques and therefore will not be detected as individual compounds. 2D liquid chromatography (2D-LC) has demonstrated applicability in difficult separations of small molecules and compounds in complex mixtures. It was hypothesized that this technique could also be used to separate co-eluting isomeric and structurally related, non-isomeric NPS, including synthetic cannabinoids (SC). Initial studies assessed several parameters, including column type, mobile phase, analysis time, gradient and flow rate, to optimize a 2D-LC method for separation and analysis of SC. The final comprehensive on-line 2D-LC method employed a Bonus-RP column in the first dimension (1D) coupled with UV detection and a biphenyl column in the second dimension (2D) coupled with QTOF-MS detection in full scan positive mode. To test the utility of the method, three SC mixes were created, each containing five compounds that were unresolvable in a traditional, 1D-LC separation; one mix with isomeric compounds and two with structurally related but non-isomeric compounds. Contour plots of UV absorbance in 1D and MS ion intensity in 2D demonstrated that all components in each mixture were successfully resolved using the 2D-LC separation method. This research serves as proof-of-concept for the application of 2D-LC to the separation of isomeric and structurally related SC. With further optimization and validation, 2D-LC may be a generally useful tool for separation of complex mixtures of NPS.
Re-estimating the relationship between inequality and growth
Authors: Scholl Nathalie , Klasen Stephan 
Published: September 2018

Abstract
In this paper, we revisit the inequality–growth relationship using an enhanced panel data set with improved inequality data. We explicitly take into account the special role of transition (post-Soviet) countries and add an instrumental variable (IV) estimation to add a causal interpretation to our findings. Our analysis is based on the specification used by Forbes in her 2000 paper, but we also address functional form concerns raised by Banerjee and Duflo three years later. We arrive at three main findings: First, the significant positive association between inequality and economic growth in the full sample is entirely driven by transition countries. Second, this relationship in transition countries is not robust to the inclusion of separate time effects. Lastly, it appears that this association is not causal but rather driven by the particular timing of the transition. Results from IV estimation confirm our interpretation of the observed positive relationship in the overall sample as non-causal.
Functional heterogeneity of lymphocytic patterns in primary melanoma dissected through single-cell multiplexing
Authors: Maria Bosisio Francesca , Antoranz Asier , van Herck Yannick , Maria Bolognesi Maddalena , Marcelis Lukas , Chinello Clizia , Wouters Jasper , Magni Fulvio , Alexopoulos Leonidas , Stas Marguerite , Boecxstaens Veerle , Bechter Oliver , Cattoretti Giorgio , van den Oord Joost 
Published: September 2018

AbstractIn melanoma, the lymphocytic infiltrate is a prognostic parameter classified morphologically into “brisk”, “non-brisk” and “absent” entailing a functional association that has never been proved. Recently, it has been shown that lymphocytic populations can be very heterogeneous, and that anti-PD-1 immunotherapy supports activated T cells. Here, we characterize the immune landscape in primary melanoma by high-dimensional single cell multiplex analysis in tissue sections (MILAN technique) followed by image analysis, RT-PCR and shotgun proteomics. We observed that the brisk and non-brisk patterns are heterogeneous functional categories that can be further sub-classified into active, transitional or exhausted. The classification of primary melanomas based on the functional paradigm also shows correlation with spontaneous regression, and an improved prognostic value than that of the brisk classification. Finally, the main inflammatory cell subpopulations that are present in the microenvironment associated with activation and exhaustion and their spatial relationships are described using neighbourhood analysis.
Thermal selection drives biodiversity origination across the Atlantic/Indian Ocean boundary
Authors: Teske Peter R. , Sandoval-Castillo Jonathan , Golla Tirupathi Rao , Emami-Khoyi Arsalan , Tine Mbaye , Heyden Sophie von der , Beheregaray Luciano B. 
Published: September 2018

AbstractIntraspecific genetic structure in widely distributed marine species often mirrors the boundaries between temperature-defined bioregions. This suggests that the same thermal gradients that maintain distinct species assemblages also drive the evolution of new biodiversity. Ecological speciation scenarios are often invoked to explain such patterns, but the fact that adaptation is usually only identified when phylogenetic splits are already evident makes it impossible to rule out the alternative scenario of allopatric speciation with subsequent adaptation. We integrated large-scale genomic and environmental datasets along one of the world’s best defined marine thermal gradients (the South African coastline) to test the hypothesis that incipient speciation in the sea is due to divergence linked to the thermal environment. We identified temperature-associated gene regions in a coastal fish species that is spatially homogeneous throughout several temperature-defined biogeographical regions on the basis of selectively neutral markers. Based on these gene regions, the species is divided into geographically distinct regional populations. Importantly, the ranges of these populations are delimited by the same ecological boundaries that define distinct infraspecific genetic lineages in co-distributed marine the species, and biogeographical disjunctions in species assemblages. Our results indicate that ecologically-mediated selection represents an early stage of marine speciation in coastal regions that lack physical dispersal barriers.
Haemophilus, Antibiotic Therapy and the Airway Microbiome in Chronic Obstructive Pulmonarydisease
Authors: Brill Simon E , James Phillip L , Cuthbertson Leah , Zhu Ana , Lawley Trevor , Cookson William OCM , Cox Michael J , Wedzicha Jadwiga A , Moffatt Miriam F 
Published: September 2018

ABSTRACTChronic obstructive pulmonary disease (COPD) is a smoking-related illness affecting 64 million people worldwide. Airway infection drives recurrent exacerbations and lung function decline. Prophylactic antibiotics may prevent exacerbations but their use is a significant cause of population antimicrobial resistance.We characterised the sputum microbiome by 16S rRNA gene analysis using 138 samples collected during a randomised controlled trial of prophylactic antibiotics in 71 patients with stable COPD. On comparing the profile of the microbiome obtained by sequencing to the isolates grown from samples using standard culture, there were similarities overall, although with a much narrower spectrum of genera on culture with under-representation of certain genera includingVeillonellaandPrevotella.There was concordance in the most abundant genera within samples and the number of isolates cultured reflected the measured bacterial diversity.We found that at baseline the microbiota of 17 (24%) patients were dominated byHaemophilus influenzae, accompanied by narrowed microbial diversity and higher levels of sputum inflammatory cytokines. DifferentH. influenzaestrains co-existed within individuals. Opportunistic whole genome sequencing of sixH. influenzaeisolates obtained during the study revealed that all were non-typeableH. influenzae(NTHI), with a range of different antibiotic resistance gene profiles, but an identical complement of virulence genes.Administration of 13 weeks prophylaxis with moxifloxacin, azithromycin or doxycycline revealed distinctive changes in microbial communities for each group.Haemophilusnumbers reduced by 90% compared to placebo only after moxifloxacin, and significant reduction in sputum cytokines occurred in patients dominated byHaemophilusat baseline.Haemophilus influenzaedominance defines COPD patients with active disease who may particularly benefit from antibiotics or vaccination.
Deciphering the enigmatic role of the amidotransferase LipL inBacillus subtilislipoic acid utilization
Authors: Rasetto Natalí B. , Lavatelli Antonela , Martin Natalia , Mansilla María Cecilia 
Published: September 2018

AbstractLipoate is an essential cofactor for key enzymes of oxidative and one-carbon metabolism. It is covalently attached to E2 subunits of dehydrogenase (DH) complexes and the GcvH subunit of the glycine cleavage system.Bacillus subtilispossess two protein lipoylation pathways: biosynthesis and scavenging. The former requires octanoylation of GcvH, amidotransfer of the octanoate to E2s, and insertion of sulfur atoms. Lipoate scavenging is mediated by a lipoate ligase (LplJ), that catalizes a classical two-step ATP-dependent reaction. Although these pathways were thought to be redundant, a ΔlipLmutant, unable to transfer the octanoyl group from GcvH to the E2s during lipoate synthesis, showed growth defects in minimal media even when supplemented with this cofactor, despite the presence of a functional LplJ. In this study we demonstrated that LipL is essential to modify E2 subunits of branched chain ketoacid and pyruvate DH during lipoate scavenging. LipL must be functional and it is not forming a complex with LplJ, which suggests that these enzymes might be acting sequentially. We also show that the E2 subunit of oxoglutarate DH is a good donor for LipL amidotransfer reaction. The essential role of LipL during lipoate utilization relies on the strict substrate specificity of LplJ, determined by charge complementarity between the ligase and the lipoylable subunits. LplJ does not recognize E2 subunits without a negatively charged residue in key positions of the target protein, and thus LipL is required to transfer the lipoate to them. This model of lipoate scavenging seems widespread among Gram-positive bacteria.
Phasor histone FLIM-FRET microscopy quantifies spatiotemporal rearrangement of chromatin architecture during the DNA damage response
Authors: Lou Jieqiong , Scipioni Lorenzo , Wright Belinda K. , Bartolec Tara K. , Zhang Jessie , Masamsetti V. Pragathi , Gaus Katharina , Gratton Enrico , Cesare Anthony J. , Hinde Elizabeth 
Published: September 2018

AbstractTo investigate how chromatin architecture is spatiotemporally organised at a double strand break (DSB) repair locus, we established a biophysical method to quantify chromatin compaction at the nucleosome level during the DNA damage response (DDR). The method is based on phasor image correlation spectroscopy (ICS) of histone FLIM-FRET microscopy data acquired in live cells co-expressing H2B-eGFP and H2B-mCherry. This multiplexed approach generates spatiotemporal maps of nuclear-wide chromatin compaction that when coupled with laser micro-irradiation induced DSBs, quantify the size, stability, and spacing between compact chromatin foci throughout the DDR. Using this technology, we identify that ATM and RNF8 regulate rapid chromatin decompaction at DSBs and formation of a compact chromatin ring surrounding the repair locus. This chromatin architecture serves to demarcate the repair locus from the surrounding nuclear environment and modulate 53BP1 mobility.SIGNIFICANCE STATEMENTChromatin dynamics play a central role in the DNA damage response (DDR). A long-standing obstacle in the DDR field was the lack of technology capable of visualising chromatin dynamics at double strand break (DSB) sites. Here we describe novel biophysical methods that quantify spatiotemporal chromatin compaction dynamics in living cells. Using these novel tools, we identify how chromatin architecture is reorganised at a DSB locus to enable repair factor access and demarcate the lesion from the surrounding nuclear environment. Further, we identify novel regulatory roles for key DDR enzymes in this process. Finally, we demonstrate method utility with physical, pharmacological and genetic manipulation of the chromatin environment, identifying method potential for use in future studies of chromatin biology.