bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of leukemic transformation in congenital neutropenia
Authors: Link Daniel C. 
Published: November 2018

Purpose of reviewThe development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia is now the major cause of mortality. Treatment options are limited and there are no effective prevention strategies. This review focuses on mechanisms of leukemic transformation in severe congenital neutropenia (SCN) and Shwachman–Diamond syndrome (SDS), the two most common types of congenital neutropenia.Recent findingsAML/MDS that develops in the setting of congenital neutropenia has distinct molecular features. Clonal hematopoiesis because ofTP53mutations is seen in nearly 50% of patients with SDS, but is not seen in patients with SCN. Accordingly, there is a very high frequency of TP53 mutations in AML/MDS arising in the setting of SDS but not SCN. The rate of mutation accumulation in hematopoietic stem cells (HSCs) from patients with congenital neutropenia is not increased.SummaryBoth HSC cell-intrinsic and noncell-intrinsic changes contribute to the development of clonal hematopoiesis in congenital neutropenia and likely accounts for the high rate of leukemic transformation. In SCN, the persistently high levels of granulocyte colony-stimulating factor drive expansion of HSCs carrying truncation mutations ofCSF3R. In SDS, impaired ribosome biogenesis induces p53-mediated growth inhibition and drives expansion of HSCs carryingTP53mutations.
Extended Use of Chimeric Medial Sural Artery Perforator Flap for 3-Dimensional Defect Reconstruction
Authors: Lee Che-Hsiung , Chang Nai-Jen Tommy , Hsiao Jo-Chun , Chu Yu-Ying , Lin Chih-Hung , Kao Huang-Kai , Lin Cheng-Hung 
Published: November 2018

Background
The medial sural artery perforator (MSAP) flap has become increasingly popular because it is thin and pliable for small to moderate defect soft tissue reconstruction. Furthermore, chimeric MSAP flap, which includes a skin paddle and a separated piece of medial gastrocnemius muscle, allowed more freedom for flap insetting, especially in 3-dimensional defect reconstruction. Here we describe our experience regarding this clinical application.

Patients and Methods
From 2007 to 2016, 14 male patients (average age, 46.9 ± 14.4 years) who received either a free or pedicled chimeric MSAP flap were included. Of these 14 patients, 7 received this flap for reconstruction in the head and neck, 2 in the upper extremities, and 5 in the lower extremities. Demographic data were collected and analyzed, and a literature review was performed.

Results
Ten patients received free chimeric MSAP flap, and 4 received the pedicled type. Thirteen of the 14 flaps (92.6%) survived, and 1 failed 2 days later owing to venous insufficiency. Venous congestion-related partial loss occurred in another case.

Conclusions
The chimeric MSAP flap is a good alternative for deep space obliteration or reconstruction of adjacent but separate defects in both free and pedicled flap design. Donor site morbidity is limited. However, the perforator needs to be mobilized carefully to prevent postoperative venous compromise.
Health Literacy Burden Is Associated With Access to Liver Transplantation
Authors: Bababekov Yanik J. , Hung Ya-Ching , Rickert Charles G. , Njoku Faith C. , Cao Bonnie , Adler Joel T. , Brega Angela G. , Pomposelli James J. , Chang David C. , Yeh Heidi 
Published: November 2018

Background.
Getting listed for liver transplantation is a complex process. Institutional health literacy may influence the ability of patients with limited educational attainment (EA) to list. As an easily accessible indicator of institutional health literacy, we measured the understandability of liver transplant center education websites and assessed whether there was any association with the percentage of low EA patients on their waitlists.

Methods.
Patients on the waitlist for liver transplantation 2007–2016 were identified in Scientific Registry of Transplant Recipients. Understandability of patient education websites was assessed using the Clear Communication Index (CCI). The Centers for Disease Control and Prevention has set itself a goal CCI of 90 as being easy to understand. Low EA was defined as less than a high school education. We adjusted for center case-mix, Donor Service Area characteristics, and EA of the general population.

Results.
Patients (84 774) were listed across 112 liver transplant centers. The median percent of waitlisted patients at each center with low EA was 11.0% (IQR, 6.6–16.8). CCI ranged from 53 to 88 and correlated with the proportion of low EA patients on the waitlist. However, CCI was not associated with the percentage of low EA in the general population. For every 1-point improvement in CCI, low EA patients increase by 0.2% (P < 0.05), translating to a 3.6% increase, or additional 3000 patients, if all centers improved their websites to CCI of 90.

Conclusions.
Educational websites that are easier to understand are associated with increased access to liver transplantation for patients with low EA. Lowering the health literacy burden by transplant centers may improve access to the liver transplant waitlist.
TGF-β2, catalase activity, H2O2 output and metastatic potential of diverse types of tumour
Authors: Haidar Malak , Metheni Mehdi , Batteux Frederic , Langsley Gordon 
Published: November 2018

AbstractTheileria annulata is a protozoan parasite that infects and transforms bovine macrophages causing a myeloid-leukaemia-like disease called tropical theileriosis. TGF-β2 is highly expressed in many cancer cells and is significantly increased in Theileria-transformed macrophages, as are levels of Reactive Oxygen Species (ROS), notably H2O2. Here, we describe the interplay between TGF-β2 and ROS in cellular transformation. We show that TGF-β2 drives expression of catalase to reduce the amount of H2O2 produced by T. annulata-transformed bovine macrophages, as well as by human lung (A549) and colon cancer (HT-29) cell lines. Theileria-transformed macrophages attenuated for dissemination express less catalase and produce more H2O2, but regain both virulent migratory and matrigel traversal phenotypes when stimulated with TGF-β2, or catalase that reduce H2O2 output. Increased H2O2 output therefore, underpins the aggressive dissemination phenotype of diverse tumour cell types, but in contrast, too much H2O2 can dampen dissemination.
ACME: Pan-specific peptide-MHC class I binding prediction through attention-based deep neural networks
Authors: Hu Yan , Wang Ziqiang , Hu Hailin , Wan Fangping , Chen Lin , Xiong Yuanpeng , Wang Xiaoxia , Zhao Dan , Huang Weiren , Zeng Jianyang 
Published: November 2018

AbstractPrediction of peptide binding to MHC molecules plays a vital role in the development of therapeutic vaccines for the treatment of cancer. Although numerous computational methods have been developed to this end, several challenges still remain in predicting peptide-MHC interactions. Many previous methods are allele-specific, training separate models for individual alleles and are thus unable to yield accurate predictions for those alleles with limited training data. Despite that there exist several pan-specific algorithms that train a common model for different alleles, they only adopt simple model structures that generally have limited performance in capturing the complex underlying patterns of peptide-MHC interactions. Here we present ACME (Attention-based Convolutional neural networks for MHC Epitope binding prediction), a new pan-specific algorithm to accurately predict the binding affinities between peptides and MHC class I molecules, even for those new alleles that are not seen in the training data. Extensive tests have demonstrated that ACME can significantly outperform other state-of-the-art prediction methods with an increase of the Pearson Correlation Coefficient by up to 23 percent. In addition, its ability to identify strong-binding peptides has been experimentally validated. Moreover, by integrating the convolutional neural network with attention mechanism, ACME is able to extract interpretable patterns that can provide useful and detailed insights into the binding preferences between peptides and their MHC partners. All these results have demonstrated that ACME can provide a powerful and practically useful tool for the studies of peptide-MHC class I interactions.
Neuropilin 1 mediates epicardial activation and revascularization in the regenerating zebrafish heart
Authors: Lowe Vanessa , Wisniewski Laura , Sayers Jacob , Frankel Paul , Mercader-Huber Nadia , Zachary Ian C , Pellet-Many Caroline 
Published: November 2018

AbstractUnlike adult mammals, zebrafish are able to naturally regenerate their heart. A key mechanism in zebrafish heart regeneration is the activation of the epicardium, leading to the establishment of a supporting scaffold for newly formed cardiomyocytes, angiogenesis and cytokine secretion. Neuropilins (NRPs) are cell surface co-receptors mediating functional signaling of kinase receptors for cytokines known to play critical roles in zebrafish heart regeneration, including Platelet-Derived growth factor (PDGF), Vascular Endothelial growth factor (VEGF), and Fibroblast growth factor (FGF). Herein, we investigated the role of neuropilins in the response of the zebrafish heart to injury and its subsequent regeneration. All four zebrafish neuropilin isoforms,nrp 1a,1b,2a, and2b, were upregulated following cardiac cryoinjury and were strongly expressed by the activated epicardium. Anrp1amutant, coding for a truncated, non-functional protein, showed a significant delay in heart regeneration in comparison to Wild-Type fish and displayed persistent collagen deposition. The regenerating hearts ofnrp1amutants were less vascularized and epicardial-derived cell migration and re-expression of the developmental gene Wilms’ tumor 1 was severely impaired innrp1amutants. Moreover, cryoinjury-induced activation and migration of epicardial cells in heart explants was strongly reduced innrp1amutant zebrafish. These results identify a key role for Nrp1 in zebrafish heart regeneration, mediated through epicardial activation, migration and revascularization.
Alterations in sialic-acid O-acetylation glycoforms during murine erythrocyte development
Authors: Mahajan Vinay S. , Alsufyani Faisal , Mattoo Hamid , Rosenberg Ian , Pillai Shiv 
Published: November 2018

ABSTRACT9-O-acetylation of sialic acid is a common modification that plays important roles in host-pathogen interactions. CASD1 has been described as a sialate-O-acetyltransferase and has been shown to be essential for 9-O-acetylation of sialic acid in some cell lines in vitro. In this study, we used knockout mice to confirm that CASD1 is indeed responsible for 9-O-acetylation of sialic acids in vivo. We observed a complete loss of 9-O-acetylation of sialic acids on the surface of myeloid, erythroid and CD4+ T cells in Casd1-deficient mice. Although 9-O-acetylation of sialic acids on multiple hematopoietic lineages was lost, there were no obvious defects in hematopoiesis. Interestingly, red blood cells from Casd1-deficient mice also lost reactivity to TER-119, a rat monoclonal antibody that is widely used to mark the murine erythroid lineage. The sialic acid glyco-epitope recognized by TER-119 on red blood cells was sensitive to the sialic acid O-acetyl esterase activity of the hemagglutinin esterase from bovine coronavirus but not to the corresponding enzyme from the influenza C virus. During erythrocyte development TER-119+ Ery-A and Ery-B cells could be stained by catalytically inactive bovine coronavirus hemaggutinin-esterase but not by the inactive influenza C hemagglutinin esterase, while TER-119+ Ery-C stage cells and mature erythrocytes were recognized by both virolectins. These results suggest that throughout murine erythrocyte development, cells of the erythroid lineage express a glycoconjugate bearing a modified 7,9-di-O-acetyl form of sialic acid, that is recognized specifically by the bovine coronavirus lectin and not by the influenza C hemagglutinin, and this modified sialic acid moiety is a component of the TER-119 epitope. As erythrocytes mature, the surface of Ery-C cells and mature erythrocytes also acquires a distinct CASD1-dependent 9-O-acetyl sialic acid moiety that can be recognized by virolectins from both influenza C and bovine coronavirus that are specific for 9-O-acetyl sialic acid.
A transcriptional cycle suited to daytime N2 fixation in the unicellular cyanobacterium Candidatus Atelocyanobacterium thalassa (UCYN-A)
Authors: Muñoz-Marin María del Carmen , Shilova Irina N. , Shi Tuo , Farnelid Hanna , Cabello Ana Maria , Zehr Jonathan P. 
Published: November 2018

AbstractThe symbiosis between a marine alga and a N2-fixing cyanobacterium (UCYN-A) is geographically widespread in the oceans and is important in the marine N cycle. UCYN-A is uncultivated, and is an unusual unicellular cyanobacterium because it lacks many metabolic functions, including oxygenic photosynthesis and carbon fixation, which are typical in cyanobacteria. It is now presumed to be an obligate symbiont of haptophytes closely related to Braarudosphaera bigelowii. N2-fìxing cyanobacteria use different strategies to avoid inhibition of N2 fixation by the oxygen evolved in photosynthesis. Most unicellular cyanobacteria temporally separate the two incompatible activities by fixing N2 only at night, but surprisingly UCYN-A appears to fix N2 during the day. The goal of this study was to determine how the unicellular UCYN-A coordinates N2 fixation and general metabolism compared to other marine cyanobacteria. We found that UCYN-A has distinct daily cycles of many genes despite the fact that it lacks two of the three circadian clock genes found in most cyanobacteria. We also found that transcription patterns in UCYN-A are most similar to marine cyanobacteria that are capable of aerobic N2 fixation in the light such as Trichodesmium and heterocyst-forming cyanobacteria, rather than Crocosphaera or Cyanothece species, which are more closely related to unicellular marine cyanobacteria evolutionarily. Our findings suggest that the symbiotic interaction has resulted in a shift of transcriptional regulation to coordinate UCYN-A metabolism with the phototrophic eukaryotic host, thus allowing efficient coupling of N2 fixation (by the cyanobacterium) to the energy obtained from photosynthesis (by the eukaryotic unicellular alga) in the light.ImportanceThe symbiotic N2-fixing cyanobacterium UCYN-A and its eukaryotic algal host, which is closely related to Braarudosphaera bigelowii, have been shown to be globally distributed and important in open ocean N2 fixation. These unique cyanobacteria have reduced metabolic capabilities, even lacking genes for oxygenic photosynthesis and carbon fixation. Cyanobacteria generally use energy from photosynthesis for nitrogen fixation, but require mechanisms for avoiding inactivation of the oxygen-sensitive nitrogenase enzyme by ambient oxygen (O2) or the O2 evolved through photosynthesis. This study shows that the symbiosis between the N2-fixing cyanobacterium UCYN-A and its eukaryotic algal host has led to adaptation of its daily gene expression pattern in order to enable daytime aerobic N2 fixation, which is likely more energetically efficient than fixing N2 at night, as in other unicellular marine cyanobacteria.
RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses
Authors: Brockmann Marisa M , Maglione Marta , Willmes Claudia G , Stumpf Alexander , Bouazza A Boris , Velasquez Laura M , Grauel Marie Katharina , Beed Prateep , Sigrist J Stephan , Rosenmund Christian , Schmitz Dietmar 
Published: November 2018

SummaryAll synapses require fusion-competent vesicles and coordinated Ca2+-secretion coupling for neurotransmission, yet functional and anatomical properties show a high diversity across different synapse types. We show here that the presynaptic protein RIM-BP2 has diversified functions in neurotransmitter release at different central mammalian synapses and thus contributes to synaptic diversity. At hippocampal pyramidal CA3-CA1 synapses, RIM-BP2 loss has a mild effect on neurotransmitter release, by only regulating Ca2+-secretion coupling. However, at hippocampal mossy fiber synapses RIM-BP2 has a strong impact on neurotransmitter release by promoting vesicle docking/priming via recruitment of Munc13-1. In wild type mossy fiber synapses, the distance between RIM-BP2 clusters and Munc13-1 clusters is larger than in hippocampal pyramidal CA3-CA1 synapses, suggesting that spatial organization may dictate the role a protein plays in synaptic transmission and that differences in active zone architecture is a major determinant factor in the functional diversity of synapses.
Towards best-practice approaches for CRISPR/Cas9 gene engineering
Authors: Van Campenhout Claude , Cabochette Pauline , Veillard Anne-Clémence , Laczik Miklos , Zelisko-Schmidt Agnieszka , Sabatel Céline , Dhainaut Maxime , Vanhollebeke Benoit , Gueydan Cyril , Kruys Véronique 
Published: November 2018

AbstractIn recent years, CRISPR has evolved from “the curious sequence of unknown biological function” into a functional genome editing tool. The CRISPR/Cas9 technology is now delivering novel genetic models for fundamental research, drug screening, therapy development, rapid diagnostics and transcriptional modulation. Despite the apparent simplicity of the CRISPR/Cas9 system, the outcome of a genome editing experiment can be substantially impacted by technical parameters as well as biological considerations. Here, we present guidelines and tools to optimize CRISPR/Cas9 genome targeting efficiency and specificity. The nature of the target locus, the design of the single guide RNA and the choice of the delivery method should all be carefully considered prior to a genome editing experiment. Different methods can also be used to detect off-target cleavages and decrease the risk of unwanted mutations. Together, these optimized tools and proper controls are essential to the assessment of CRISPR/Cas9 genome editing experiments.
Scleraxis Lineage Cells Contribute to Organized Bridging Tissue During Tendon Healing, and Identifies Subpopulations of Resident Tendon Cells
Authors: Best Katherine T. , Loiselle Alayna E. 
Published: November 2018

AbstractDuring tendon healing, it is postulated that intrinsic tendon cells drive tissue regeneration while extrinsic cells drive pathological scar formation. Intrinsic tendon cells are frequently described as a homogenous, fibroblast population that is positive for the marker Scleraxis. It is controversial whether intrinsic Scleraxis localize within the forming scar tissue during adult tendon healing. We have previously demonstrated that calcium binding protein S100a4 is a driver of tendon scar formation and marks a subset of intrinsic tendon cells. However, the relationship between Scleraxis and S100a4 has not been explored. In this study, we aimed to investigate the localization of Scleraxis lineage cells following adult murine flexor tendon repair and to establish the relationship between Scleraxis and S100a4 throughout both homeostasis and healing. We have shown that adult Scleraxis lineage cells localize within the scar tissue and organize into a highly aligned cellular bridge during tendon healing. Additionally, we demonstrate that markers Scleraxis and S100a4 label distinct populations in tendon during homeostasis and localize differently within tendon scar tissue, with Scleraxis found specifically in the organized bridging tissue and S100a4 localized throughout the entire scar region. These studies define a heterogeneous tendon cell environment and demonstrate discreet contributions of subpopulations during healing. Taken together, these data enhance our understanding and ability to target the complex cellular environment of the tendon during homeostasis and healing.
A dual function of FGF signaling inXenopusleft-right axis formation
Authors: Schneider Isabelle , Kreis Jennifer , Schweickert Axel , Blum Martin , Vick Philipp 
Published: November 2018

AbstractOrgan left-right (LR) asymmetry is a conserved vertebrate feature, which is regulated by left-sided activation of Nodal signaling. Nodal asymmetry is established by a leftward fluid-flow generated at the ciliated LR organizer (LRO). While the role of fibroblast growth factor (FGF) signaling pathways during mesoderm development are conserved, diverging results from different model organisms suggested a non-conserved function in LR asymmetry. Here, we demonstrate that FGF is required during gastrulation in a dual function at consecutive stages ofXenopusembryonic development. In the early gastrula, FGF is necessary for LRO precursor induction, acting in parallel to FGF-mediated mesoderm induction. During late gastrulation, the FGF/Ca2+-branch is required for specification of the flow sensing lateral LRO cells, a function related to FGF-mediated mesoderm morphogenesis. This second function in addition requires input from the calcium channel Polycystin-2. Thus, analogous to mesoderm development, FGF activity is required in a dual role for laterality specification, namely for generating and sensing of leftward flow. Moreover, our data show that FGF functions in LR asymmetric development are conserved across vertebrate species, from fish to mammals.
Scaling computational genomics to millions of individuals with GPUs
Authors: Taylor-Weiner Amaro , Aguet François , Haradhvala Nicholas J. , Gosai Sager , Anand Shankara , Kim Jaegil , Ardlie Kristin , Van Allen Eliezer M. , Getz Gad 
Published: November 2018

AbstractCurrent genomics methods were designed to handle tens to thousands of samples, but will soon need to scale to millions to keep up with the pace of data and hypothesis generation in biomedical science. Moreover, costs associated with processing these growing datasets will become prohibitive without improving the computational efficiency and scalability of methods. Here, we show that recently developed machine-learning libraries (TensorFlow and PyTorch) facilitate implementation of genomics methods for GPUs and significantly accelerate computations. To demonstrate this, we re-implemented methods for two commonly performed computational genomics tasks: QTL mapping and Bayesian non-negative matrix factorization. Our implementations ran > 200 times faster than current CPU-based versions, and these analyses are ∼5-10 fold cheaper on GPUs due to the vastly shorter runtimes. We anticipate that the accessibility of these libraries, and the improvements in run-time will lead to a transition to GPU-based implementations for a wide range of computational genomics methods.
scID: Identification of equivalent transcriptional cell populations across single cell RNA-seq data using discriminant analysis
Authors: Boufea Katerina , Seth Sohan , Batada Nizar N. 
Published: November 2018

AbstractThe power of single cell RNA sequencing (scRNA-seq) stems from its ability to uncover cell type-dependent phenotypes, which rests on the accuracy of cell type identification. However, resolving cell types within and, thus, comparison of scRNA-seq data across conditions is challenging due to technical factors such as sparsity, low number of cells and batch effect. To address these challenges we developed scID (Single Cell IDentification), which uses the framework of Fisher’s Linear Discriminant Analysis to identify transcriptionally related cell types between scRNA-seq datasets. We demonstrate the accuracy and performance of scID relative to existing methods on several published datasets. By increasing power to identify transcriptionally similar cell types across datasets, scID enhances investigator’s ability to extract biological insights from scRNA-seq data.