bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders
Authors: Seidlitz Jakob , Nadig Ajay , Liu Siyuan , Bethlehem Richard A.I. , Vértes Petra E. , Morgan Sarah E. , Váša František , Romero-Garcia Rafael , Lalonde François M. , Clasen Liv S. , Blumenthal Jonathan D. , Paquola Casey , Bernhardt Boris , Wagstyl Konrad , Polioudakis Damon , de la Torre-Ubieta Luis , Geschwind Daniel H. , Han Joan C. , Lee Nancy R. , Murphy Declan G. , Bullmore Edward T. , Raznahan Armin 
Published: March 2019

AbstractNeurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i)in vivoneuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorder’s anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this “transcriptional vulnerability model” by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.
Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Authors: Wang Qingbo , Pierce-Hoffman Emma , Cummings Beryl B. , Karczewski Konrad J. , Alföldi Jessica , Francioli Laurent C. , Gauthier Laura D. , Hill Andrew J. , O’Donnell-Luria Anne H. ,   Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium, MacArthur Daniel G. 
Published: March 2019

AbstractMulti-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools for variant interpretation typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,996,125 MNVs across the genome with constituent variants falling within 2 bp distance of one another, of which 31,510 exist within the same codon, including 405 predicted to result in gain of a nonsense mutation, 1,818 predicted to rescue a nonsense mutation event that would otherwise be caused by one of the constituent variants, and 16,481 additional variants predicted to alter protein sequences. We show that the distribution of MNVs is highly non-uniform across the genome, and that this non-uniformity can be largely explained by a variety of known mutational mechanisms, such as CpG deamination, replication error by polymerase zeta, or polymerase slippage at repeat junctions. We also provide an estimate of the dinucleotide mutation rate caused by polymerase zeta. Finally, we show that differential CpG methylation drives MNV differences across functional categories. Our results demonstrate the importance of incorporating haplotype-aware annotation for accurate functional interpretation of genetic variation, and refine our understanding of genome-wide mutational mechanisms of MNVs.
Biomarkers for capturing disease pathology as molecular process hyperstructure
Authors: Lukas Arno , Heinzel Andreas , Mayer Bernd 
Published: March 2019

AbstractBackgroundPrecision of drugs in clinical development but also of approved treatment sees limits, documented as attrition in clinical stage drug testing and suboptimal number needed to treat in clinical practice. Precision medicine aims at approaching a causal relation of disease pathology, treatment mechanism of action and clinical outcome. The instance linking pathology, clinical phenotype and drug response is disease characteristics amenable for quantitation, including established clinical phenotyping parameters and upcoming molecular profiling and biomarkers. Molecular biomarkers situated at the interface of pathology-specific molecular process architecture and drug mechanism of action promise capturing aspects allowing assessment of treatment response.ResultsApproximating a set of 1,008 disease terms as pathology molecular networks provides 3,860 molecular processes involving 4,602 protein coding genes. Assembling this process set in a hierarchical cluster using mean shortest paths among processes as distance measure allows representation of molecular processes in cumulative aggregation. This procedure transforms human disease pathology into a static instance of a molecular process hyperstructure involving 1,340 aggregate levels in a molecular architecture. The hyperstructure allows evaluating molecular biomarker candidates at different levels of molecular process aggregation in terms of biomarker-specific entropies. Interpretation as information content reflects the capacity of a biomarker for sensing molecular process configuration.Deriving entropies across aggregation levels for a reference set of 1,502 biomarker candidates identifies significant spread in information content of individual biomarkers. Exemplified on biomarker panels holding evidence for prognostic capacity and factors serving as drug targets from selected chronic diseases, biomarker entropies allow interpretation in terms of sensitivity for capturing process context and specificity for informing on the status of individual processes afflicted with a given pathology.ConclusionsHigh entropy biomarkers provide candidate molecular proxies for clinical phenotyping parameters, and low entropy biomarkers add information on specifics of disease pathology. Combining high and low entropy biomarkers in panels may offer relevant resolution of molecular process configurations for improving patient stratification with respect to minimizing variance in drug response.
The Mut+strain ofKomagataella phaffii(Pichia pastoris) expresses PAOX15 and 10 times faster than Mutsand Mut−strains: Evidence that formaldehyde or/and formate are true inducers of AOX
Authors: Singh Anamika , Narang Atul 
Published: March 2019

AbstractThe methylotrophic yeastKomagataella phaffiiis among the most popular hosts for recombinant protein synthesis. Most recombinant proteins were expressed in the wild-type Mut+host strain from the methanol-inducible promoter PAOX1. Since methanol metabolism has undesirable consequences, two additional host strains, Muts(AOX1-) and Mut−(AOX1-AOX2-), were introduced which consume less methanol and reportedly also express recombinant protein better than Mut+. Both results follow from a simple model based on two widespread assumptions, namely methanol is transported by diffusion and the sole inducer of PAOX1. To test this model, we studied14C-methanol uptake in the Mut−strain and β-galactosidase expression in all three strains. We confirmed that methanol is transported by diffusion, but in contrast to the literature, Mut+expressed β-galactosidase 5- and 10-fold faster than Mutsand Mut−. These results imply that methanol is not the sole inducer of PAOX1— metabolites downstream of methanol also induce PAOX1. We find that formate or/and formaldehyde are probably true inducers since both induce PAOX1expression in Mut−which cannot synthesize intracellular methanol from formate or formaldehyde. Formate offers a promising substitute for methanol since it does not appear to suffer from the deficiencies that afflict methanol.
Evaluation of extraction solvents for untargeted metabolomics analysis of enrichment reactor cultures performing enhanced biological phosphorus removal (EBPR)
Authors: Thaw Saw Nay Min Min , Suwanchaikasem Pipob , Zuniga-Montanez Rogelio , Qiu Guanglei , Wuertz Stefan , Williams Rohan B. H. 
Published: March 2019

AbstractIntroductionThe extraction solvent mixtures were optimized for untargeted metabolomics analysis of microbial communities from two laboratory scale activated sludge reactors performing enhanced biological phosphorus removal (EBPR).ObjectiveTo develop a robust and simple analytical protocol to analyse microbial metabolomics from EBPR bioreactors.MethodsExtra- and intra-cellular metabolites were extracted using five methods and analysed by ultraperformance liquid chromatography mass spectrometry (UPLC-MS).ResultsThe optimal extraction method was biomass specific and methanol:water (1:1 v/v) and methanol:chloroform:water (2:2:1 v/v) were chosen, respectively, for each of the two different bioreactors.ConclusionOur approach provides direct surveys of the metabolic state of PAO-enriched EBPR communities, showing that extraction methods should be carefully tailored to the microbial community under study
Low temperature triggers genome-wide hypermethylation of transposable elements and centromeres in maize
Authors: Achour Zeineb , Joets Johann , Leguilloux Martine , Sellier Hélène , Pichon Jean-Philippe , Leveugle Magalie , Duborjal Hervé , Caius José , Brunaud Véronique , Roux Christine Paysant-Le , Mary-Huard Tristan , Giauffret Catherine , Vitte Clémentine 
Published: March 2019

ABSTRACTCharacterizing the molecular processes developed by plants to respond to environmental cues is a major task to better understand local adaptation. DNA methylation is a chromatin mark involved in the transcriptional silencing of transposable elements (TEs) and gene expression regulation. While the molecular bases of DNA methylation regulation are now well described, involvement of DNA methylation in plant response to environmental cues remains poorly characterized. Here, using the TE-rich maize genome and analyzing methylome response to prolonged cold at the chromosome and feature scales, we investigate how genomic architecture affects methylome response to stress in a cold-sensitive genotype. Interestingly, we show that cold stress induces a genome-wide methylation increase through the hypermethylation of TE sequences and centromeres. Our work highlights a cytosine context-specific response of TE methylation that depends on TE types, chromosomal location and proximity to genes. The patterns observed can be explained by the parallel transcriptional activation of multiple DNA methylation pathways that methylate TEs in the various chromatin locations where they reside. Our results open new insights into the possible role of genome-wide DNA methylation in phenotypic response to stress.
Regional brain development analysis through registration using anisotropic similarity, a constrained affine transformation
Authors: Legouhy Antoine , Commowick Olivier , Proisy Maïa , Rousseau François , Barillot Christian 
Published: March 2019

AbstractWe propose a novel method to quantify brain growth in 3 arbitrary orthogonal directions of the brain or its sub-regions through linear registration. This is achieved by introducing a 9 degrees of freedom (dof) transformation called anisotropic similarity which is an affine transformation with constrained scaling directions along arbitrarily chosen orthogonal vectors. This gives the opportunity to extract scaling factors describing brain growth along those directions by registering a database of subjects onto a common reference. This information about directional growth brings insights that are not usually available in longitudinal volumetry analysis. The interest of this method is illustrated by studying the anisotropic regional and global brain development of 308 healthy subjects betwen 0 and 19 years old. A gender comparison of those scaling factors is also performed for 4 classes of age. We demonstrate through these applications the stability of the method to the chosen reference and its ability to highlight growth differences accros regions and gender.
Procaine and S-adenosyl-L-homocysteine (SAH) affect the expression of genes related to the epigenetic machinery and change the DNA methylation status ofin vitrocultured bovine skin fibroblasts
Authors: N.A.B. Schumann , Mendonça A.S. , Silveira M.M. , Vargas L.N. , Leme L.O. , de Sousa R.V. , Franco M.M. 
Published: March 2019

AbstractCloning using somatic cell nuclear transfer (SCNT) has many potential applications such as in transgenic and genomic-edited animal production. Abnormal epigenetic reprogramming of somatic cell nuclei is probably the major cause of the low efficiency associated with SCNT. Strategies to alter DNA reprogramming in donor cell nuclei may help improve the cloning efficiency. In the present study, we aimed to characterise the effects of procaine and S-adenosyl-L-homocysteine (SAH) as demethylating agents during the cell culture of bovine skin fibroblasts. We characterised the effects of procaine and SAH on the expression of genes related to the epigenetic machinery, including the DNMT1, DNMT3A, DNMT3B, TET1, TET2, TET3, and OCT4 genes, and on DNA methylation levels of bovine skin fibroblasts. We found that DNA methylation levels of satellite I were reduced by SAH (P=0.0495) and by the combination of SAH and procaine (P=0.0479) compared with that in the control group. Global DNA methylation levels were lower in cells that were cultivated with both compounds than in control cells [procaine (P=0.0116), SAH (P=0.0408), and both (P=0.0163)]. Regarding the transcriptional profile, there was a decrease in total DNMT transcript levels in cells cultivated with SAH and procaine. There was a higher level of TET3 transcripts in treated cells than in the controls. Our results showed that the use of procaine and SAH during bovine cell culture was able to alter the epigenetic profile of the cells. This approach may be a useful alternative strategy to improve the efficiency of reprogramming the somatic nuclei after fusion, which in turn will improve the SCNT efficiency.
In vitro evaluation of probiotic properties of lactic acid bacteria isolated from some traditionally fermented Ethiopian food products
Authors: Mulaw Guesh , Sisay Tesfaye , Muleta Diriba , Tesfaye Anteneh 
Published: March 2019

AbstractProbiotics are live microorganisms which when consumed in large number together with a food promote the health of the consumer. The aim of this study was to evaluatein vitroprobiotic properties of lactic acid bacteria (LAB) isolated from traditional Ethiopian fermentedTeff injeradough,ErgoandKochoproducts. A total of 90 LAB were isolated, of which 4 (4.44%) isolates showed 45.35-97.11% and 38.40-90.49% survival rate at pH values (2, 2.5 and 3) for 3 and 6 h in that order. The four acid tolerant isolates were found tolerant to 0.3% bile salt for 24 h with 91.37 to 97.22% rate of survival. The acid-and-bile salt tolerant LAB isolates were found inhibiting some foodborne test pathogenic bacteria to varying degrees. All acid-and-bile tolerant isolates displayed varying sensitivity to different antibiotics. Thein vitroadherence to stainless steel plates of the 4 screened probiotic LAB isolates were ranged from 32.75 to 36.30% adhesion rate. The four efficient probiotic LAB isolates that belonged toLactobacillusspecies were identified to strain level using 16S rDNA gene sequence comparisons and namely wereLactobacillus plantarumstrain CIP 103151,Lactobacillus paracaseisubsp. tolerans strain NBRC 15906,Lactobacillus paracaseistrain NBRC 15889 andLactobacillus plantarumstrain JCM 1149. The fourLactobacillusstrains were found to have potentially useful to produce probiotic products.
Quadriceps and hamstrings coactivation in exercises used in prevention and rehabilitation of hamstring strain injury in young soccer players
Authors: Torres Gonzalo , Chorro David , Navandar Archit , Rueda Javier , Fernández Luís , Navarro Enrique 
Published: March 2019

AbstractThis study aimed to study the co-activation of hamstring-quadriceps muscles during submaximal strength exercises without the use of maximum voluntary isometric contraction testing and compare (i) the inter-limb differences in muscle activation, (ii) the intra-muscular group activation pattern, and (iii) the activation during different phases of the exercise. Muscle activation was recorded by surface electromyography of 19 elite male youth players. Participants performed five repetitions of the Bulgarian squat, lunge and the squat with an external load of 10 kg. Electrical activity was recorded for the rectus femoris, vastus medialis, vastus lateralis, biceps femoris and semitendinosus. No significant inter-limb differences were found (F1, 13=619;p=0.82; partial η2=0.045). Significant differences were found in the muscle activation between different muscles within the muscle group (quadriceps and hamstrings) for each of the exercises: Bulgarian squat (F1,18=331:p<0.001; partial η2=0.80), lunge (F4,72=114.5; p<0.001; partial η2=0.86) and squat (F1,16=247.31;p<0.001; partial η2=0.93).Differences were found between the concentric, isometric and eccentric phases of each of the exercises (F2, 26=52.27;p=0.02; partial η2=0.80). The existence of an activation pattern of each of the muscles in the three proposed exercises could be used for muscle assessment and as a tool for injury recovery.
Diet composition of introduced Barn Owls (Tyto alba javanica) in urban area in comparison with agriculture settings
Authors: Saufi Safwan , Ravindran Shakinah , Hamid Noor Hisham , Zainal Abidin Cik Mohd Rizuan , Ahmad Hamdan , Ahmad Abu Hassan , Salim Hasber 
Published: March 2019

AbstractThis study investigated the diet of introduced barn owls (Tyto alba javanica, Gmelin) in the urban area of the Main Campus of Universiti Sains Malaysia, Penang, Malaysia, based on collected regurgitated pellets. We also compared the diet of introduced urban barn owls with the diet of barn owls from two agricultural areas, i.e. oil palm plantations and rice fields. Pellet analysis of barn owls introduced in the urban area showed that commensal Norway rats,Rattus norvegicus, made up the highest proportion of the diet (65.37% prey biomass) while common shrews,Suncus murinuswere the second highest consumed prey (30.12% prey biomass). Common plantain squirrel,Callosciurus notatus, made up 4.45% of the diet while insects were taken in a relatively small amount (0.046% prey biomass). Introduced barn owls showed a preference for medium-sized prey, i.e. 40 to 120g (52.96% biomass and 38.71% total). In agricultural areas,Rattus argentiventerpredominated the diet of barn owls (98.24% prey biomass) in rice fields while Malayan wood rats,Rattus tiomanicus, were the most consumed prey in oil palm plantations (99.5% prey biomass). Food niche breadth value was highest for barn owls introduced in an urban area with a value of 2.90, and 1.06 in rice fields and 1.22 in oil palm plantations. Our analysis reiterates the prey preference of barn owls in various landscapes for small mammals. Our results also indicate the suitability of utilizing barn owls as a biological control not only in agricultural areas, but also as a biological control agent for commensal rodent pests in urban areas.
Multimorbidity and healthcare utilization: A register-based study in Denmark
Authors: Frølich Anne , Ghith Nermin , Schiøtz Michaela , Jacobsen Ramune , Stockmarr Anders 
Published: March 2019

AbstractBackgroundPeople with multimorbidity have reduced functional capacity, lower quality of life, and higher mortality rates and use healthcare resources more intensively than healthy people or those with a single chronic condition. The aim of this study was to explore associations between multimorbidity and use of healthcare services and the impact of socioeconomic status on utilization of hospitalizations and bed days.MethodsThe study population included all individuals aged 16 years and older who lived in the Capital Region of Denmark on January 1st, 2012. Data on chronic conditions, use of healthcare services and demographics were obtained from Danish national administrative and health registries. Zero-inflated models were used to calculate anticipated annual use of hospitalizations and bed days.FindingsThe study population comprised 1,397,173 individuals; the prevalence of multimorbidity was 22%. Prevalence was inversely related to educational attainment. For people with multimorbidity, utilization of hospitalizations and bed days increased approximately linearly with the number of chronic conditions. However, a steep increase in utilization of bed days was observed between five and six or more chronic conditions. An educational gradient in hospitalization rates and use of bed days was observed regardless of the number of chronic conditions. Educational attainment was strongly associated with healthcare utilization.ConclusionMultimorbidity was associated with a significant increase in utilization of all healthcare services in Denmark. In addition, a socioeconomic gradient was observed in utilization of hospitalizations and bed days.
A mathematical model of Campylobacter dynamics within a broiler flock
Authors: Rawson Thomas , Dawkins Marian Stamp , Bonsall Michael B. 
Published: March 2019

AbstractGlobally, the bacterial genusCampylobacteris one of the leading causes of human gastroenteritis, with its primary route of infection being through poultry meat. Despite decades of study we appear to be no closer to preventing outbreaks within commercial chicken flocks, and the application of biosecurity measures is limited by a lack of understanding of the transmission dynamics within a flock. Our work is the first to undertake a mathematical modelling approach toCampylobacterpopulation dynamics within a flock of broilers (chickens bred specifically for meat). A system of stochastic differential equations is used to investigate the diverse and fluctuating conditions within the gut of a broiler, and models the routes of infection between co-housed birds. The presented model provides mechanistic explanations for key infection dynamics that have been long-observed but very poorly understood. We highlight several driving mechanisms behind observed infection phenomena, simulate experimentally observed inter-strain competition, and present a promising approach to hypothesising new methods of preventing flock outbreaks.Author summaryThe bacteriaCampylobacteris one of the most common causes of food poisoning globally. The most common route of infection is through raw chicken meat, as a result of many chicken farms across the world housing fully infected flocks. Despite the magnitude of this public health risk, little is understood of the specifics of how chickens become infected, and the ways that they then infect one another. Our work presents a mathematical model ofCampylobactertransmission dynamics within a flock of chickens. We compare the results of the model to real world data sets, explore key dynamical behaviours, and present a sensitivity analysis to highlight the most important factors underpinning outbreaks.