bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination
Authors: Fine Amena Smith , Nemeth Christina L. , Kaufman Miriam L. , Fatemi Ali 
Published: December 2019

Abstract
Background
The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively.

Body
The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum.

Conclusion
The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.
Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome
Authors: Aziz Nadine M. , Klein Jenny A. , Brady Morgan R. , Olmos-Serrano Jose Luis , Gallo Vittorio , Haydar Tarik F. 
Published: December 2019

AbstractBackgroundDown syndrome (DS), caused by the triplication of chromosome 21, results in a constellation of clinical features including changes in intellectual and motor function. Although altered neural development and function have been well described in people with DS, few studies have investigated the etiology underlying the observed motor phenotypes. Here, we examine the development, patterning, and organization of the spinal cord throughout life in the Ts65Dn mouse, a model that recapitulates many of the motor changes observed in people with DS.MethodsSpinal cords from embryonic to adult animals were processed for gene and protein expression (immunofluorescence) to track the spatiotemporal development of excitatory and inhibitory neurons and oligodendroglia. Postnatal analyses were focused on the lumbar region due to the reflex and gait abnormalities found in Ts65Dn mice and locomotive alterations seen in people with DS.ResultsBetween embryonic days E10.5 and E14.5, we found a larger motor neuron progenitor domain in Ts65Dn animals containing more OLIG2-expressing progenitor cells. These disturbed progenitors are delayed in motor neuron production but eventually generate a large number of ISL1+ migrating motor neurons. We found that higher numbers of PAX6+ and NKX2.2+ interneurons (INs) are also produced during this time frame. In the adult lumbar spinal cord, we found an increased level ofHb9and a decreased level ofIrx3gene expression in trisomic animals. This was accompanied by an increase in Calretinin+ INs, but no changes in other neuronal populations. In aged Ts65Dn animals, both Calbindin+ and ChAT+ neurons were decreased compared to euploid controls. Additionally, in the dorsal corticospinal white matter tract, there were significantly fewer CC1+ mature OLs in 30- and 60-day old trisomic animals and this normalized to euploid levels at 10–11 months. In contrast, the mature OL population was increased in the lateral funiculus, an ascending white matter tract carrying sensory information. In 30-day old animals, we also found a decrease in the number of nodes of Ranvier in both tracts. This decrease normalized both in 60-day old and aged animals.ConclusionsWe show marked changes in both spinal white matter and neuronal composition that change regionally over the life span. In the embryonic Ts65Dn spinal cord, we observe alterations in motor neuron production and migration. In the adult spinal cord, we observe changes in oligodendrocyte maturation and motor neuron loss, the latter of which has also been observed in human spinal cord tissue samples. This work uncovers multiple cellular perturbations during Ts65Dn development and aging, many of which may underlie the motor deficits found in DS.
Accuracy of genomic BLUP when considering a genomic relationship matrix based on the number of the largest eigenvalues: a simulation study
Authors: Pocrnic Ivan , Lourenco Daniela A. L. , Masuda Yutaka , Misztal Ignacy 
Published: December 2019

AbstractBackgroundThe dimensionality of genomic information is limited by the number of independent chromosome segments (Me), which is a function of the effective population size. This dimensionality can be determined approximately by singular value decomposition of the gene content matrix, by eigenvalue decomposition of the genomic relationship matrix (GRM), or by the number of core animals in the algorithm for proven and young (APY) that maximizes the accuracy of genomic prediction. In the latter, core animals act as proxies to linear combinations ofMe. Field studies indicate that a moderate accuracy of genomic selection is achieved with a small dataset, but that further improvement of the accuracy requires much more data. When only one quarter of the optimal number of core animals are used in the APY algorithm, the accuracy of genomic selection is only slightly below the optimal value. This suggests that genomic selection works on clusters ofMe.ResultsThe simulation included datasets with different population sizes and amounts of phenotypic information. Computations were done by genomic best linear unbiased prediction (GBLUP) with selected eigenvalues and corresponding eigenvectors of the GRM set to zero. About four eigenvalues in the GRM explained 10% of the genomic variation, and less than 2% of the total eigenvalues explained 50% of the genomic variation. With limited phenotypic information, the accuracy of GBLUP was close to the peak where most of the smallest eigenvalues were set to zero. With a large amount of phenotypic information, accuracy increased as smaller eigenvalues were added.ConclusionsA small amount of phenotypic data is sufficient to estimate only the effects of the largest eigenvalues and the associated eigenvectors that contain a large fraction of the genomic information, and a very large amount of data is required to estimate the remaining eigenvalues that account for a limited amount of genomic information. Core animals in the APY algorithm act as proxies of almost the same number of eigenvalues. By using an eigenvalues-based approach, it was possible to explain why the moderate accuracy of genomic selection based on small datasets only increases slowly as more data are added.
The importance of controlled mating in honeybee breeding
Authors: Plate Manuel , Bernstein Richard , Hoppe Andreas , Bienefeld Kaspar 
Published: December 2019

Abstract
Background
Controlled mating procedures are widely accepted as a key aspect of successful breeding in almost all animal species. In honeybees, however, controlled mating is hard to achieve. Therefore, there have been several attempts to breed honeybees using free-mated queens. In such breeding schemes, selection occurs only on the maternal path since the drone sires are random samples of the population. The success rates of breeding approaches without controlled mating have so far not been investigated on a theoretical or simulation-based level.

Methods
Stochastic simulation studies were carried out to examine the chances of success in honeybee breeding with and without controlled mating. We investigated the influence of different sizes of breeding populations (500, 1000, 2000 colonies per year) and unselected passive populations (0, 500, 1000, 2000, infinitely many colonies per year) on selection for a maternally (queen) and directly (worker group) influenced trait with moderate ($$r_{md}=-\,0.53$$rmd=-0.53) or strong ($$r_{md}=-\,0.88$$rmd=-0.88) negative correlation between the two effects. The simulations described 20 years of selection.

Results
Our simulations showed a reduction of breeding success between 47 and 99% if mating was not controlled. In the most drastic cases, practically no genetic gain could be generated without controlled mating. We observed that in the trade-off between selection for direct or maternal effects, the absence of mating control leads to a shift in favor of maternal effects. Moreover, we describe the implications of different breeding strategies on the unselected passive population that benefits only indirectly via the transfer of queens or drones from the breeding population. We show that genetic gain in the passive population develops parallel to that of the breeding population. However, we found a genetic lag that became significantly smaller as more breeding queens served as dams of queens in the passive population.

Conclusions
We conclude that even when unwanted admixture of subspecies can be excluded in natural matings, controlled mating is imperative for successful breeding efforts. This is especially highlighted by the strong positive impact that controlled mating in the breeding population has on the unselected passive population.
EvoFreq: visualization of the Evolutionary Frequencies of sequence and model data
Authors: Gatenbee Chandler D. , Schenck Ryan O. , Bravo Rafael R. , Anderson Alexander R. A. 
Published: December 2019

AbstractBackgroundHigh throughput sequence data has provided in depth means of molecular characterization of populations. When recorded at numerous time steps, such data can reveal the evolutionary dynamics of the population under study by tracking the changes in genotype frequencies over time. This necessitates a simple and flexible means of visualizing an increasingly complex set of data.ResultsHere we offer EvoFreq as a comprehensive tool set to visualize the evolutionary and population frequency dynamics of clones at a single point in time or as population frequencies over time using a variety of informative methods. EvoFreq expands substantially on previous means of visualizing the clonal, temporal dynamics and offers users a range of options for displaying their sequence or model data.ConclusionsEvoFreq, implemented in R with robust user options and few dependencies, offers a high-throughput means of quickly building, and interrogating the temporal dynamics of hereditary information across many systems. EvoFreq is freely available viahttps://github.com/MathOnco/EvoFreq.
Predicting associations among drugs, targets and diseases by tensor decomposition for drug repositioning
Authors: Wang Ran , Li Shuai , Cheng Lixin , Wong Man Hon , Leung Kwong Sak 
Published: December 2019

Abstract
Background
Development of new drugs is a time-consuming and costly process, and the cost is still increasing in recent years. However, the number of drugs approved by FDA every year per dollar spent on development is declining. Drug repositioning, which aims to find new use of existing drugs, attracts attention of pharmaceutical researchers due to its high efficiency. A variety of computational methods for drug repositioning have been proposed based on machine learning approaches, network-based approaches, matrix decomposition approaches, etc.

Results
We propose a novel computational method for drug repositioning. We construct and decompose three-dimensional tensors, which consist of the associations among drugs, targets and diseases, to derive latent factors reflecting the functional patterns of the three kinds of entities. The proposed method outperforms several baseline methods in recovering missing associations. Most of the top predictions are validated by literature search and computational docking. Latent factors are used to cluster the drugs, targets and diseases into functional groups. Topological Data Analysis (TDA) is applied to investigate the properties of the clusters. We find that the latent factors are able to capture the functional patterns and underlying molecular mechanisms of drugs, targets and diseases. In addition, we focus on repurposing drugs for cancer and discover not only new therapeutic use but also adverse effects of the drugs. In the in-depth study of associations among the clusters of drugs, targets and cancer subtypes, we find there exist strong associations between particular clusters.

Conclusions
The proposed method is able to recover missing associations, discover new predictions and uncover functional clusters of drugs, targets and diseases. The clustering of drugs, targets and diseases, as well as the associations among the clusters, provides a new guiding framework for drug repositioning.
Thymol tolerance in Escherichia coli induces morphological, metabolic and genetic changes
Authors: Al-Kandari Fatemah , Al-Temaimi Rabeah , van Vliet Arnoud H. M. , Woodward Martin J. 
Published: December 2019

Abstract
Background
Thymol is a phenolic compound used for its wide spectrum antimicrobial activity. There is a limited understanding of the antimicrobial mechanisms underlying thymol activity. To investigate this, E. coli strain JM109 was exposed to thymol at sub-lethal concentrations and after 16 rounds of exposure, isolates with a 2-fold increased minimal inhibitory concentration (MIC) were recovered (JM109-Thyr). The phenotype was stable after multiple sub-cultures without thymol.

Results
Cell morphology studies by scanning electron microscopy (SEM) suggest that thymol renders bacterial cell membranes permeable and disrupts cellular integrity. 1H Nuclear magnetic resonance (NMR) data showed an increase in lactate and the lactic acid family amino acids in the wild type and JM109-Thyr in the presence of thymol, indicating a shift from aerobic respiration to fermentation. Sequencing of JM109-Thyr defined multiple mutations including a stop mutation in the acrR gene resulting in a truncation of the repressor of the AcrAB efflux pump. AcrAB is a multiprotein complex traversing the cytoplasmic and outer membrane, and is involved in antibiotic clearance.

Conclusions
Our data suggests that thymol tolerance in E. coli induces morphological, metabolic and genetic changes to adapt to thymol antimicrobial activity.
Role of membrane compartment occupied by Can1 (MCC) and eisosome subdomains in plant pathogenicity of the necrotrophic fungus Alternaria brassicicola
Authors: Colou Justine , N’Guyen Guillaume Quang , Dubreu Ophélie , Fontaine Kévin , Kwasiborski Anthony , Bastide Franck , Manero Florence , Hamon Bruno , Aligon Sophie , Simoneau Philippe , Guillemette Thomas 
Published: December 2019

AbstractBackgroundMCC/eisosomes are membrane microdomains that have been proposed to participate in the plasma membrane function in particular by regulating the homeostasis of lipids, promoting the recruitment of specific proteins and acting as provider of membrane reservoirs.ResultsHere we showed that several potential MCC/eisosomal protein encoding genes in the necrotrophic fungusA. brassicicolawere overexpressed when germinated spores were exposed to antimicrobial defence compounds, osmotic and hydric stresses, which are major constraints encountered by the fungus during the plant colonization process. Mutants deficient for key MCC/eisosome components did not exhibit any enhanced susceptibility to phytoalexins and to applied stress conditions compared to the reference strain, except for a slight hypersensitivity of the∆∆abpil1a-abpil1bstrain to 2 M sorbitol. Depending on the considered mutants, we showed that the leaf and silique colonization processes were impaired by comparison to the wild-type, and assumed that these defects in aggressiveness were probably caused by a reduced appressorium formation rate.ConclusionsThis is the first study on the role of MCC/eisosomes in the pathogenic process of a plant pathogenic fungus. A link between these membrane domains and the fungus ability to form functional penetration structures was shown, providing new potential directions for plant disease control strategies.
Comparison of emergence agitation between succinylcholine and rocuronium-sugammadex in adults following closed reduction of a nasal bone fracture: a prospective randomized controlled trial
Authors: Lee Seok-Jin , Sung Tae-Yun , Cho Choon-Kyu 
Published: December 2019

AbstractBackgroundSugammadex allows rapid recovery from rocuronium-induced neuromuscular blockade. Succinylcholine is often used for brief surgeries but is associated with myalgia, headache, histamine release, and increased lactate levels. Thus, we hypothesized that succinylcholine may affect emergence agitation (EA) and compared the effects of succinylcholine and rocuronium-sugammadex on EA in patients undergoing closed reduction of a nasal bone fracture under general anesthesia.MethodsForty-two patients were prospectively enrolled and allocated randomly to the succinylcholine group (group SC) or the rocuronium-sugammadex group (group RS; eachn = 21). Neuromuscular block and its reversal were achieved with succinylcholine and normal saline in group SC, whereas rocuronium and sugammadex were administered in group RS. After surgery, the incidence of EA as a primary outcome, the incidence of dangerous EA, and duration of EA as secondary outcomes were compared.ResultsThe incidence of EA was higher in group SC than in group RS (90.5% vs. 47.6%, respectively; relative risk [RR] 4.3; 95% confidence interval [CI] 1.2 to 15.7;P = .006). The incidence of dangerous EA increased in group SC compared to group RS (33.3% vs. 4.8%, respectively; RR 2.1; 95% CI 1.3 to 3.4;P = .045). The duration of agitation was longer in group SC than in group RS [106.5 (65.1) vs. 40.4 (26.0) sec; mean difference 66.1 s; 95% CI 31.0 to 101.1; effect size 1.3;P = .001).ConclusionSuccinylcholine increases the incidence, severity, and duration of EA compared to rocuronium-sugammadex in patients undergoing closed reduction of a nasal bone fracture.Trial registrationCRiS Registration numberKCT0002673. Initial registration date was 31 January 2018 (Retrospectively registered).
Opportunities and barriers for providing HIV testing through community health centers in mainland China: a nationwide cross-sectional survey
Authors: Ong Jason J. , Peng Ming Hui , Wong William W. , Lo Ying-Ru , Kidd Michael R. , Roland Martin , Zhu Shan Zhu , Jiang Sun Fang 
Published: December 2019

Abstract
Background
Primary care may be an avenue to increase coverage of HIV testing but it is unclear what challenges primary healthcare professionals in low- and middle-income countries face. We describe the HIV testing practices in community health centres (CHCs) and explore the staff’s attitude towards further development of HIV testing services at the primary care level in China.

Methods
We conducted a national, cross-sectional survey using a stratified random sample of CHCs in 20 cities in 2015. Questionnaires were completed by primary care doctors and nurses in CHCs, and included questions regarding their demographics, clinical experience and their views on the facilitators and barriers to offering HIV testing in their CHC. Multivariate logistic regression was conducted to examine the association between staff who would offer HIV testing and their sociodemographic characteristics.

Results
A total of 3580 staff from 158 CHCs participated. Despite the majority (81%) agreeing that HIV testing was an important part of healthcare, only 25% would provide HIV testing when requested by a patient. The majority (71%) were concerned about reimbursement, and half (47%) cited lack of training as a major barrier. Almost half (44%) believed that treating people belonging to high-risk populations would scare other patients away, and 6% openly expressed their dislike of people belonging to high-risk populations. Staff who would offer HIV testing were younger (adjusted odds ratio (aOR) 0.97 per year increase in age, 95% confidence interval (CI):0.97–0.98); trained as a doctor compared to a nurse (aOR 1.79, 95%CI:1.46–2.15); held a bachelor degree or above (aOR 1.34, 95%CI:1.11–1.62); and had previous HIV training (aOR 1.55, 95%CI:1.27–1.89).

Conclusions
Improving HIV training of CHC staff, including addressing stigmatizing attitudes, and improving financial reimbursement may help increase HIV testing coverage in China.
An investigation of oxidant/antioxidant balance in patients with migraine: a case-control study
Authors: Togha Mansoureh , Razeghi Jahromi Soodeh , Ghorbani Zeinab , Ghaemi Amir , Rafiee Pegah 
Published: December 2019

Abstract
Background
In recent years, the role of neuroinflammation and oxidative stress in migraine pathogenesis has achieved considerable interest; however, to date findings are equivocal. Thus, the objective of this study was to investigate biomarkers of oxidative stress in episodic and chronic migraineurs (EM and CM patients) and controls.

Methods
Forty-four patients with EM, 27 individuals with CM and 19 age-sex-matched controls were enrolled. After collecting data on demographic and headache characteristics, blood samples were collected and analyzed to detect serum levels of oxidative stress biomarkers (malondialdehyde (MDA) and nitric oxide (NO)); total antioxidant capacity using Trolox equivalent antioxidant capacity (TEAC) assay; and antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase-1 (GPx-1)).

Results
Serum levels of CAT and SOD were significantly lower in the CM group than the EM group and controls. However, serum GPx-1 levels of the CM patients were slightly higher than the EM patients and controls (P-value≤0.001). CM patients had lower mean TEAC values than EM patients and controls. In addition, serum levels of NO and MDA were significantly elevated among subjects with CM compared to EM and control individuals (P-value≤0.001). Pearson correlation analysis revealed negative correlations between the number of days of having headaches per month and serum concentrations of the two antioxidant enzymes CAT (r = − 0.60, P-value< 0.001) and SOD (r = − 0.50, P-value< 0.001) as well as TEAC values (r = − 0.61, P-value< 0.001); however, there were positive correlations between headache days and serum GPx-1 levels (r = 0.46, P-value< 0.001), NO (r = 0.62, P-value< 0.001), and MDA (r = 0.64, P-value< 0.001).

Conclusion
Present findings highlighted that chronic migraineurs had lower total non-enzymatic antioxidant capacity and higher oxidative stress than episodic migraineurs and control individuals. Although more studies are needed to confirm these data, applying novel prophylactic medications or dietary supplements with antioxidant properties could be promising in migraine therapy.