bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lost in translation: bioinformatic analysis of variations affecting the translation initiation codon in the human genome
Authors: Abad-Navarro Francisco , de la Morena-Barrio María Eugenia , Fernández-Breis Jesualdo Tomás , Corral Javier 
Published: May 2018

Abstract

Motivation
Translation is a key biological process controlled in eukaryotes by the initiation AUG codon. Variations affecting this codon may have pathological consequences by disturbing the correct initiation of translation. Unfortunately, there is no systematic study describing these variations in the human genome. Moreover, we aimed to develop new tools for in silico prediction of the pathogenicity of gene variations affecting AUG codons, because to date, these gene defects have been wrongly classified as missense.

Results
Whole-exome analysis revealed the mean of 12 gene variations per person affecting initiation codons, mostly with high (&gt;0.01) minor allele frequency (MAF). Moreover, analysis of Ensembl data (December 2017) revealed 11 261 genetic variations affecting the initiation AUG codon of 7205 genes. Most of these variations (99.5%) have low or unknown MAF, probably reflecting deleterious consequences. Only 62 variations had high MAF. Genetic variations with high MAF had closer alternative AUG downstream codons than did those with low MAF. Besides, the high-MAF group better maintained both the signal peptide and reading frame. These differentiating elements could help to determine the pathogenicity of this kind of variation.

Availability and implementation
Data and scripts in Perl and R are freely available at https://github.com/fanavarro/hemodonacion.

Supplementary information
Supplementary data are available at Bioinformatics online.
Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions
Authors: Lionakis Michail S , Lewis Russell E , Kontoyiannis Dimitrios P 
Published: May 2018

Abstract
Although the widespread use of mold-active agents (especially the new generation of triazoles) has resulted in reductions of documented invasive mold infections (IMIs) in patients with hematological malignancies and allogeneic hematopoietic stem cell transplantation (HSCT), a subset of such patients still develop breakthrough IMIs (bIMIs). There are no data from prospective randomized clinical trials to guide therapeutic decisions in the different scenarios of bIMIs. In this viewpoint, we present the current status of our understanding of the clinical, diagnostic, and treatment challenges of bIMIs in high-risk adult patients with hematological cancer and/or HSCT receiving mold-active antifungals and outline common clinical scenarios. As a rule, managing bIMIs demands an individualized treatment plan that takes into account the host, including comorbidities, certainty of diagnosis and site of bIMIs, local epidemiology, considerations for fungal resistance, and antifungal pharmacological properties. Finally, we highlight areas that require future investigation in this complex area of clinical mycology.
Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation
Authors: Iwasaki Kenta , Kitahata Nana , Hiramitsu Takahisa , Yamamoto Takayuki , Noda Takayuki , Okada Manabu , Narumi Shunji , Watarai Yoshihiko , Miwa Yuko , Uchida Kazuharu , Matsuoka Yutaka , Horimi Kosei , Kobayashi Takaaki 
Published: May 2018

Abstract
It is unclear to what extent the development of follicular helper T cells (Tfh) and de novo donor-specific human leukocyte antigen antibody (DSA) production could be influenced by immunosuppressive agents, particularly calcineurin inhibitor (CNI; cyclosporine or tacrolimus), after kidney transplantation. Here, the effects of immunosuppressive agents on Tfh-mediated B-cell activation and antibody production were investigated. In vitro circulating Tfh (cTfh; memory CD4+CXCR5+)/B-cell (CD19+) co-culture assays revealed that CNI considerably inhibited cTfh-mediated B-cell activation and IgG antibody secretion through the suppression of IL-21 and IL-2. Both IL-21 and CD40L up-regulated IL-2 receptors (CD25) on B cells, and anti-CD25 antibody induced apoptosis of activated B cells, resulting in the inhibition of IgG production. The frequency of cTfh-expressed CD40L and PD-1 was elevated in patients with de novo DSA 1 year after transplantation. The degree of inhibition by CNI was dependent on Staphylococcal enterotoxin B-induced CD40L+PD-1+ cTfh up-regulation level. Our data demonstrate that CD40L+PD-1+cTfh could be a marker to implicate individual difference in CNI sensitivity for Tfh-mediated B-cell activation in kidney transplantation.
Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials
Authors: Idzerda Nienke M A , Pena Michelle J , Parving Hans-Henrik , de Zeeuw Dick , Heerspink Hiddo J L 
Published: May 2018

Abstract

Background
Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline.

Methods
The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14 weeks and whether these responses were predictive of eGFR decline during the subsequent 9 months of follow-up.

Results
UPCR and TC response varied between individuals: mean UPCR response was −1.3% (5th–95th percentile −59.9 to 141.8) and mean TC response was −93.9 mg/dL (−169.1 to −26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) −1.6 to 0.9; P = 0.54] and TC responders (0.3; 95% CI −1.8 to 1.1; P = 0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6–3.0; P = 0.004 and 1.7; 95% CI 0.5–2.9; P = 0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5–3.7; P = 0.01). These findings were not different for rosuvastatin or atorvastatin.

Conclusions
Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.
Arterial spin labeling MR imaging for differentiation between high- and low-grade glioma—a meta-analysis
Authors: Falk Delgado Alberto , De Luca Francesca , van Westen Danielle , Falk Delgado Anna 
Published: May 2018

Abstract

Background
Arterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) non-invasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma.

Methods
Cochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed.

Results
In total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79–0.90) and specificity 0.80 (0.72–0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71–0.91) and specificity 0.83 (0.69–0.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79–0.91) and specificity 0.80 (0.65–0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered.

Conclusion
Arterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.
Inertial Measurement Unit-Assisted Implantation of Pedicle Screws in Combination With an Intraoperative 3-Dimensional/2-Dimensional Visualization of the Spine
Authors: Jost Gregory F , Walti Jonas , Mariani Luigi , Schaeren Stefan , Cattin Philippe 
Published: May 2018

Abstract

BACKGROUND
Inertial measurement units (IMUs) are microelectromechanical systems used to track orientation and motion.

OBJECTIVE
To use instruments mounted with IMUs in combination with a 3- and 2-dimensional (3D/2D) rendering of the computed-tomography scan (CT) to guide implantation of pedicle screws.

METHODS
Pedicle screws were implanted from T1 to S1 in 2 human cadavers. A software application enabled the surgeon to select the starting points and trajectories on a 3D/2D image of the spine, then locate these starting points on the exposed spine and apply the IMU-mounted instruments to reproduce the trajectories. The position of the screws was evaluated on the postoperative CT scan.

RESULTS
A total of 72 pedicle screws were implanted. Thirty-seven (77%) of the thoracic screws were within the pedicle (Heary I), 7 (15%) showed a lateral breach of the pedicle, and 4 (8%) violated the anterior or lateral vertebral body (Heary III). In the lumbar spine and S1, 21 screws (88%) were within the pedicle (Gertzbein 0), 2 (8%) screws had a pedicle wall breach < 2 mm (Gertzbein 1), and 1 > 2 to < 4 mm (Gertzbein 2). In the second cadaver, the position was compared to the intraoperatively shown virtual position. The median offset was 3°(mean 3° ± 2°, variance 5, range 0°–9°) in the sagittal plane and 3° (mean 4° ± 3°, variance 9, range 0°–12°) in the axial plane.

CONCLUSION
IMU-assisted implantation of pedicle screws combined with an intraoperative 3D/2D visualization of the spine enabled the surgeon to precisely implant pedicle screws on the exposed spine.
“Interlocking” Clipping of an Irregular Middle Cerebral Artery Bifurcation Aneurysm: 2-Dimensional Operative Video
Authors: Sorenson Thomas J , Marcellino Chris , Acciarri Nicola , Rangel Castilla Leonardo , Lanzino Giuseppe 
Published: May 2018

Abstract
Middle cerebral artery (MCA) aneurysms often have an irregular morphology that might require creative clipping techniques even in the case of small aneurysms. In this video, we illustrate the case of a patient with an incidental but very irregular MCA aneurysm. The presence of 2 separate, asymmetric lobes was dealt with by utilizing the “interlocking” clip technique in which a regular clip is used to obliterate 1 portion of the aneurysm and a fenestrated clip, with the ring of the fenestration circling the body of the first clip, is used to obtain obliteration of the other lobe. This patient also had a contralateral internal carotid artery occlusion, and we discuss the pitfalls of temporary clipping in such a situation.
Genomic Analysis of a Transcriptional Networks Directing Progression of Cell States During MGE development
Authors: Sandberg Magnus , Taher Leila , Hu Jiaxin , Black Brian L. , Nord Alex , Rubenstein John L.R. 
Published: May 2018

ABSTRACTBackgroundHomeodomain (HD) transcription factor (TF) NKX2-1 critical for the regional specification of the medial ganglionic eminence (MGE) as well as promoting the GABAergic and cholinergic neuron fates via the induction of TFs such as LHX6 and LHX8. NKX2-1 defines MGE regional identity in large part through transcriptional repression, while specification and maturation of GABAergic and cholinergic fates is mediated in part by transcriptional activation via TFs such as LHX6 and LHX8. Here we analyze the signaling and TF pathways, downstream of NKX2-1, required for GABAergic and cholinergic neuron fate maturation.MethodsDifferential ChIP-seq analysis was used to identify regulatory elements (REs) where chromatin state was sensitive to change in theNkx2-1cKO MGE at embryonic day (E) 13.5. TF motifs in the REs were identified using RSAT. CRISPR-mediated genome editing was used to generate enhancer knockouts. Differential gene expression in these knockouts was analyzed through RT-qPCR and in situ hybridization. Functional analysis of motifs within hs623 was analyzed via site directed mutagenesis and reporter assays in primary MGE cultures.ResultsWe identified 4782 activating REs (aREs) and 6391 repressing REs (rREs) in theNkx2-1conditional knockout (Nkx2-1cKO) MGE. aREs are associated with basic-Helix-Loop-Helix (bHLH) TFs. Deletion of hs623, an intragenicTcf12aRE, caused a reduction ofTcf12expression in the sub-ventricular zone (SVZ) and mantle zone (MZ) of the MGE. Mutation of LHX, SOX and octamers, within hs623, caused a reduction of hs623 activity in MGE primary cultures.ConclusionsTcf12expression in the sub-ventricular zone (SVZ) of the MGE is mediated through aRE hs623. The activity of hs623 is dependent on LHX6, SOX and octamers. Thus, maintaining the expression ofTcf12in the SVZ involves on TF pathways parallel and genetically downstream of NKX2-1.
Sex differences along the Autism Continuum: A twin study of brain structure
Authors: Cauvet Élodie , Westeinde Annelies van’t , Toro Roberto , Kuja-Halkola Ralf , Neufeld Janina , Mevel Katell , Bölte Sven 
Published: May 2018

ABSTRACTFemales might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N=148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.
Quantitative assessment of cell population diversity in single-cell landscapes
Authors: Liu Qi , Herring Charles A. , Sheng Quanhu , Ping Jie , Simmons Alan J. , Chen Bob , Banerjee Amrita , Gu Guoqiang , Coffey Robert J. , Shyr Yu , Lau Ken S. 
Published: May 2018

AbstractSingle-cell RNA-sequencing (scRNA-seq) has become a powerful tool for the systematic investigation of cellular diversity. As a number of computational tools have been developed to identify and visualize cell populations within a single scRNA-seq dataset, there is a need for methods to quantitatively and statistically define proportional shifts in cell population structures across datasets, such expansion or shrinkage, or emergence or disappearance of cell populations. Here we present sc-UniFrac, a framework to statistically quantify compositional diversity in cell populations between single-cell transcriptome landscapes. sc-UniFrac enables sensitive and robust quantification in simulated and experimental datasets in terms of both population identity and quantity. We have demonstrated the utility of sc-UniFrac in multiple applications, including assessment of biological and technical replicates, classification of tissue phenotypes, identification and definition of altered cell populations, and benchmarking batch correction tools. sc-UniFrac provides a framework for quantifying diversity or alterations in cell populations across conditions, and has broad utility for gaining insight on how cell populations respond to perturbations.
Atxn2-CAG100-knock-in affects mouse lifespan and vestibulo-cerebellar function via neural disconnection
Authors: Halbach Melanie V. , Sen Nesli-Ece , Canet-Pons Júlia , Kuppens Bram W. , Segers Mandy , Schonewille Martijn , Rollmann Ewa , Seidel Kay , Rüb Udo , Meierhofer David , Mittelbronn Michel , Harter Patrick , De Zeeuw Chris I. , Almaguer-Mederos Luis E. , Gispert Suzana , Bosman Laurens W.J. , Auburger Georg 
Published: May 2018

AbstractUnstable expansions in the Q22-polyglutamine domain of human ATXN2 mediate risks for motor neuron diseases such as ALS/FTLD or cause the autosomal dominant Spinocerebellar Ataxia type 2 (SCA2), but the pathogenesis is not understood and models are unavailable.We generated a novel knock-in mouse line with CAG100 expansion inAtxn2, transmitted unstably. The mutant protein accumulated in neuronal cytosolic aggregates, with a characteristic pattern of multi-system-atrophy. Loss-of-function phenotypes included less mutant offspring, initial weight gain and motor hyperactivity. Progressive toxic aggregation effects started around 20 weeks in homozygous animals showing weight loss, reduced muscle strength and gait ataxia. Lifespan was decreased. In the cerebellum, neuronal soma and dendrites were remarkably spared. However, myelin proteins MBP, CNP, PLP1 and transcriptsMal, Mobp, Rtn4decreased markedly, especially adhesion factors MAG and MOG. In neurons, strong reductions were found for mRNAs of perineuronal elementsHaplnl, Hapln2, Hapln4, of axonal myelin interactorsPrnpandKlk6. At protein level, the adhesion factor neuroplastin and neurofilaments were strongly reduced, while presynaptic alpha-synuclein increased two-fold.Overall, this authentic SCA2 mouse model elucidates how altered function and aggregation toxicity of ATXN2 conspire to trigger axon-myelin disconnection. This model will promote the development of neuroprotective therapies and disease biomarkers.
Analysing the structure of pathways and its influence on the interpretation of biomedical datasets
Authors: Burger Bram , Hernández Sánchez Luis Francisco , Lereim Ragnhild Reehorst , Barsnes Harald , Vaudel Marc 
Published: May 2018

SummaryBiochemical pathways are commonly used as a reference to conduct functional analysis on biomedical omics datasets, where experimental results are mapped to knowledgebases comprising known molecular interactions collected from the literature. Due to their central role, the content of the functional knowledgebases directly influences the outcome of pathway analyses. In this study, we investigate the structure of the current pathway knowledge, as exemplified by Reactome, discuss the consequences for biological interpretation, and outline possible improvements in the use of pathway knowledgebases. By providing a view of the underlying network structure, we aim to help pathway analysis users manage their expectations and better identify possible artefacts in the results.
Nuclear and mitochondrial phylogenomics of the Diplostomoidea and Diplostomida (Digenea, Platyhelminthes)1
Authors: Locke Sean A. , Dam Alex Van , Caffara Monica , Pinto Hudson Alves , López-Hernández Danimar , Blanar Christopher 
Published: May 2018

AbstractHigher systematics within the Digenea, Carus 1863 have been relatively stable since a phylogenetic analysis of partial nuclear ribosomal markers (rDNA) led to the erection of the Diplostomida Olson, Cribb, Tkach, Bray, and Littlewood, 2003. However, recent mitochondrial (mt) genome phylogenies suggest this order might be paraphyletic. These analyses show members of two diplostomidan superfamilies are more closely related to the Plagiorchiida La Rue, 1957 than to other members of the Diplostomida. In one of the groups implicated, the Diplostomoidea Poirier, 1886, a recent phylogeny based on mt DNA also indicates the superfamily as a whole is non-monophyletic. To determine if these results were robust to additional taxon sampling, we analyzed mt genomes from seven diplostomoids in three families. To choose between phylogenetic alternatives based on mt genomes and the prior rDNA-based topology, we also analyzed hundreds of ultra-conserved elements (UCEs) assembled from shotgun sequencing. The Diplostomida was paraphyletic in the mt genome phylogeny, but supported in the UCE phylogeny. We speculate this mitonuclear discordance is related to ancient, rapid radiation in the Digenea. Both UCEs and mt genomes support the monophyly of the Diplostomoidea and show congruent relationships within it. The Cyathocotylidae Mühling, 1898 are early diverging descendants of a paraphyletic clade of Diplostomidae Poirier, 1886, in which were nested members of the Strigeidae Railliet, 1919; the results support prior suggestions that the Crassiphialinae Sudarikov, 1960 will rise to the family level. Morphological traits of diplostomoid metacercariae appear to be more useful for differentiating higher taxa than those of adults. We describe a new species of Cotylurus Szidat, 1928, resurrect a species of Hysteromorpha Lutz, 1931, and find support for a species of Alaria Schrank, 1788 of contested validity. Complete rDNA operons are provided as a resource for future studies.
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
Authors: Cortés-Ciriano Isidro , Lee June-Koo , Xi Ruibin , Jain Dhawal , Jung Youngsook L. , Yang Lixing , Gordenin Dmitry , Klimczak Leszek J. , Zhang Cheng-Zhong , Pellman David S. , Park Peter J. ,   on behalf of the PCAWG Structural Variation Working Group,   the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
Published: May 2018

SummaryChromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.