bluuebunny/crossref_metadata_2025_split huggingface dataset:
New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0
Authors: Clark Alex M , Sarker Malabika , Ekins Sean 
Published: August 2014

Abstract

Background
We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible.

Results
We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a näive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets.

Conclusions

TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool.
Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells
Authors: Thorn Mitchell , Point Gary R , Burga Rachel A , Nguyen Cang T , Joseph Espat N , Katz Steven C 
Published: August 2014

ABSTRACTLM escape immune surveillance, in part, as a result of the expansion of CD11b+MC, which alter the intrahepatic microenvironment to promote tumor tolerance. HBC make up a significant proportion of liver lymphocytes and appear to delay tumor progression; however, their significance in the setting of LM is poorly defined. Therefore, we characterized HBC and HBC/CD11b+MC interactions using a murine model of LM. Tumor-bearing livers showed a trend toward elevated absolute numbers of CD19+ HBC. A significant increase in the frequency of IgMloIgDhi mature HBC was observed in mice with LM compared with normal mice. HBC derived from tumor-bearing mice demonstrated increased proliferation in response to TLR and BCR stimulation ex vivo compared with HBC from normal livers. HBC from tumor-bearing livers exhibited significant down-regulation of CD80 and were impaired in inducing CD4+ T cell proliferation ex vivo. We implicated hepatic CD11b+MC as mediators of CD80 down-modulation on HBC ex vivo via a CD11b-dependent mechanism that required cell-to-cell contact and STAT3 activity. Therefore, CD11b+MC may compromise the ability of HBC to promote T cell activation in the setting of LM as a result of diminished expression of CD80. Cross-talk between CD11b+MC and HBC may be an important component of LM-induced immunosuppression.
Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531
Authors: Gamis Alan S. , Alonzo Todd A. , Meshinchi Soheil , Sung Lillian , Gerbing Robert B. , Raimondi Susana C. , Hirsch Betsy A. , Kahwash Samir B. , Heerema-McKenney Amy , Winter Laura , Glick Kathleen , Davies Stella M. , Byron Patti , Smith Franklin O. , Aplenc Richard 
Published: August 2014

PurposeTo improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.Patients and MethodsChildren, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).ResultsThere were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P = .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).ConclusionGO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.
The tattered curtain hypothesis revised: Coastal jets limit cross‐shelf larval transport
Authors: Harrison Cheryl S. , Siegel David A. 
Published: August 2014

Lay AbstractThis biophysical modeling study examined how ocean currents control transport of simulated larvae and the relationship of coastal larval retention to wind forcing. We found that offshore transport was limited when an alongshore coastal jet of water was in place. This jet exhibited complex topology, remaining parallel to the coast for wide sections while simultaneously meandering and “tattering” in other regions. After long periods of strong wind forcing, the jet broke up and larvae moved offshore in complex patterns. However, the integrated strength of the wind only moderately predicted coastal retention of simulated larvae, suggesting that the jet dynamics are intrinsically nonlinear. Coastal jets are expected to exert a strong control on coastal transport in a variety of settings.
Rab35 promotes the recruitment of Rab8, Rab13 and Rab36 to recycling endosomes through MICAL-L1 during neurite outgrowth
Authors: Kobayashi Hotaka , Etoh Kan , Ohbayashi Norihiko , Fukuda Mitsunori 
Published: August 2014

ABSTRACT
Small GTPase Rab35 is an important molecular switch for endocytic recycling that regulates various cellular processes, including cytokinesis, cell migration, and neurite outgrowth. We previously showed that active Rab35 promotes nerve growth factor (NGF)-induced neurite outgrowth of PC12 cells by recruiting MICAL-L1, a multiple Rab-binding protein, to Arf6-positive recycling endosomes. However, the physiological significance of the multiple Rab-binding ability of MICAL-L1 during neurite outgrowth remained completely unknown. Here we report that Rab35 and MICAL-L1 promote the recruitment of Rab8, Rab13, and Rab36 to Arf6-positive recycling endosomes during neurite outgrowth. We found that Rab35 functions as a master Rab that determines the intracellular localization of MICAL-L1, which in turn functions as a scaffold for Rab8, Rab13, and Rab36. We further showed by functional ablation experiments that each of these downstream Rabs regulates neurite outgrowth in a non-redundant manner downstream of Rab35 and MICAL-L1, e.g. by showing that knockdown of Rab36 inhibited recruitment of Rab36-specific effector JIP4 to Arf6-positive recycling endosomes, and caused inhibition of neurite outgrowth without affecting accumulation of Rab8 and Rab13 in the same Arf6-positive area. Our findings suggest the existence of a novel mechanism that recruits multiple Rab proteins at the Arf6-positive compartment by MICAL-L1.
A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer
Authors: Burman Jonathon L. , Itsara Leslie S. , Kayser Ernst-Bernhard , Suthammarak Wichit , Wang Adrienne M. , Kaeberlein Matt , Sedensky Margaret M. , Morgan Philip G. , Pallanck Leo J. 
Published: August 2014

Abstract
Mutations affecting mitochondrial complex I, a multi-subunit assembly that couples electron transfer to proton pumping, are the most frequent cause of heritable mitochondrial diseases. However, the mechanisms by which complex I dysfunction results in disease remain unclear. Here, we describe a Drosophila model of complex I deficiency caused by a homoplasmic mutation in the mitochondrial-encoded NADH dehydrogenase subunit 2 (ND2) gene. We show that ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential, and lower levels of neural ATP. Our biochemical studies of ND2 mutants reveal that complex I is unable to efficiently couple electron transfer to proton pumping. Thus, our study provides evidence that the ND2 subunit participates directly in the proton pumping mechanism of complex I. Together, our findings support the model that diminished respiratory chain activity, and consequent energy deficiency, are responsible for the pathogenesis of complex I-associated neurodegeneration.
Modelling of a targeted nanotherapeutic ‘stroma’ to deliver the cytokine LIF, or XAV939, a potent inhibitor of Wnt–β-catenin signalling, for use in human fetal dopaminergic grafts in Parkinson’s disease
Authors: Zhao Jing-Wei , Dyson Sean C. , Kriegel C. , Tyers Pam , He Xiaoling , Fahmy Tarek M. , Metcalfe Su M. , Barker Roger A. 
Published: August 2014

Abstract
The endogenous reparative capacity of the adult human brain is low, and chronic neurodegenerative disorders of the central nervous system represent one of the greatest areas of unmet clinical need in the developing world. Novel therapeutic strategies to treat them include: (i) growth factor delivery to boost endogenous repair and (ii) replacement cell therapy, including replacing dopaminergic neurons to treat Parkinson's disease (PD). However, these approaches are restricted not only by rapid degradation of growth factors, but also by the limited availability of cells for transplant and the poor survival of implanted cells that lack the necessary stromal support. We therefore hypothesised that provision of a transient artificial stroma for paracrine delivery of pro-survival factors could overcome both of these issues. Using leukaemia inhibitory factor (LIF) - a proneural, reparative cytokine - formulated as target-specific poly(lactic-co-glycolic acid) (PLGA) nano-particles (LIF-nano-stroma), we discovered that attachment of LIF-nano-stroma to freshly isolated fetal dopaminergic cells improved their survival fourfold: furthermore, in vivo, the number of surviving human fetal dopaminergic cells tended to be higher at 3 months after grafting into the striatum of nude rats, compared with controls treated with empty nanoparticles. In addition, we also analysed the effect of a novel nano-stroma incorporating XAV939 (XAV), a potent inhibitor of the developmentally important Wnt-β-catenin signalling pathway, to investigate whether it could also promote the survival and differentiation of human fetal dopaminergic precursors; we found that the numbers of both tyrosine-hydroxylase-positive neurons (a marker of dopaminergic neurons) and total neurons were increased. This is the first demonstration that LIF-nano-stroma and XAV-nano-stroma each have pro-survival effects on human dopaminergic neurons, with potential value for target-specific modulation of neurogenic fate in cell-based therapies for PD
Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming
Authors: Zwaans Bernadette M. M. , Lombard David B. 
Published: August 2014

AbstractIn the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.
Isolating the role of elevated Phlda2 in asymmetric late fetal growth restriction in mice
Authors: Tunster Simon J. , Van De Pette Matthew , John Rosalind M. 
Published: August 2014

Abstract
Pleckstrin homology-like domain family A member 2 (PHLDA2) is a maternally expressed imprinted gene whose elevated expression has been linked to fetal growth restriction in a number of human studies. In mice, Phlda2 negatively regulates placental growth and limits the accumulation of placental glycogen. We previously reported that a three-copy transgene spanning the Phlda2 locus drove a fetal growth restriction phenotype late in gestation, suggesting a causative role for PHLDA2 in human growth restriction. However, in this mouse model, Phlda2 was overexpressed by fourfold, alongside overexpression of a second imprinted gene, Slc22a18. Here, we genetically isolate the role of Phlda2 in driving late fetal growth restriction in mice. We furthermore show that this Phlda2-driven growth restriction is asymmetrical, with a relative sparing of the brain, followed by rapid catch-up growth after birth, classic features of placental insufficiency. Strikingly, fetal growth restriction showed strain-specific differences, being apparent on the 129S2/SvHsd (129) genetic background and absent on the C57BL6 (BL6) background. A key difference between these two strains is the placenta. Specifically, BL6 placentae possess a more extensive endocrine compartment and substantially greater stores of placental glycogen. Taken together, these data support a direct role for elevated Phlda2 in limiting fetal growth but also suggest that growth restriction only manifests when there is limited placental reserve. These findings should be taken into account in interpreting the results from human studies.
The use of MRI in pre-operative evaluation of anterior talofibular ligament in chronic ankle instability
Authors: Kanamoto T. , Shiozaki Y. , Tanaka Y. , Yonetani Y. , Horibe S. 
Published: August 2014

Objectives To evaluate the applicability of MRI for the quantitative assessment of anterior talofibular ligaments (ATFLs) in symptomatic chronic ankle instability (CAI). Methods Between 1997 and 2010, 39 patients with symptomatic CAI underwent surgical treatment (22 male, 17 female, mean age 25.4 years (15 to 40)). In all patients, the maximum diameters of the ATFLs were measured on pre-operative T2-weighted MR images in planes parallel to the path of the ATFL. They were classified into three groups based on a previously published method with modifications: ‘normal’, diameter = 1.0 - 3.2 mm; ‘thickened’, diameter > 3.2 mm; ‘thin or absent’, diameter < 1.0 mm. Stress radiography was performed with the maximum manual force in inversion under general anaesthesia immediately prior to surgery. In surgery, ATFLs were macroscopically divided into two categories: ‘thickened’, an obvious thickened ligament and ‘thin or absent’. The imaging results were compared with the macroscopic results that are considered to be of a gold standard. Results Agreement was reached when comparison was made between groups, based on MRI and macroscopic findings. ATFLs were abnormal in all 39 cases and classified as ten ‘thickened’ and 29 ‘thin or absent’. As to talar tilt stress radiography, a clear cut-off angle, which would allow discrimination between ‘thickened’ and ‘thin or absent’ patients, was not identified. Conclusion MRI is valuable as a pre-operative assessment tool that can provide the quantitative information of ATFLs in patients with CAI. Cite this article Bone Joint Res 2014;3:241–5.
Gender differences and age-related changes in body fat mass in Tibetan children and teenagers: an analysis by the bioelectrical impedance method
Authors: Zhang Hai-Long , Fu Qiang , Li Wen-Hui , Liu Su-Wei , Zhong Hua , Duoji Bai-Ma , Zhang Mei-Zhi , Lv Po , Xi Huan-Jiu 
Published: August 2014

AbstractWe aimed to obtain the fat base value and the fat distribution characteristics of Tibetan children and teenagers by estimating their body fat content with the bioelectrical impedance method.We recruited 1427 healthy children and teenagers by a stratified cluster sampling method. By using bioelectrical impedance analysis, we obtained various values relevant to fat.We found that total body fat mass and the fat mass of various body parts increased with age in boys and girls. Yet there were no differences between age groups until 11 years. However, fat mass increased quickly between 11 and 18 years, and significant differences were seen between adolescent boys and girls; all fat indices were higher in girls than in boys (p<0.05).The characteristics of fat in Tibetan children and teenagers in Tibet is related to age and gender related hormone secretion, which reflects the physiological characteristics in different developmental stages.
Negative control of BAK1 by protein phosphatase 2A during plant innate immunity
Authors: Segonzac Cécile , Macho Alberto P , Sanmartín Maite , Ntoukakis Vardis , Sánchez‐Serrano José Juan , Zipfel Cyril 
Published: August 2014

AbstractRecognition of pathogen‐associated molecular patterns (PAMPs) by surface‐localized pattern‐recognition receptors (PRRs) activates plant innate immunity, mainly through activation of numerous protein kinases. Appropriate induction of immune responses must be tightly regulated, as many of the kinases involved have an intrinsic high activity and are also regulated by other external and endogenous stimuli. Previous evidences suggest that PAMP‐triggered immunity (PTI) is under constant negative regulation by protein phosphatases but the underlying molecular mechanisms remain unknown. Here, we show that protein Ser/Thr phosphatase type 2A (PP2A) controls the activation of PRR complexes by modulating the phosphostatus of the co‐receptor and positive regulator BAK1. A potential PP2A holoenzyme composed of the subunits A1, C4, and B’η/ζ inhibits immune responses triggered by several PAMPs and anti‐bacterial immunity. PP2A constitutively associates with BAK1 in planta. Impairment in this PP2A‐based regulation leads to increased steady‐state BAK1 phosphorylation, which can poise enhanced immune responses. This work identifies PP2A as an important negative regulator of plant innate immunity that controls BAK1 activation in surface‐localized immune receptor complexes.
UBL5 is essential for pre‐mRNA splicing and sister chromatid cohesion in human cells
Authors: Oka Yasuyoshi , Varmark Hanne , Vitting‐Seerup Kristoffer , Beli Petra , Waage Johannes , Hakobyan Anna , Mistrik Martin , Choudhary Chunaram , Rohde Mikkel , Bekker‐Jensen Simon , Mailand Niels 
Published: August 2014

AbstractUBL5 is an atypical ubiquitin‐like protein, whose function in metazoans remains largely unexplored. We show that UBL5 is required for sister chromatid cohesion maintenance in human cells. UBL5 primarily associates with spliceosomal proteins, and UBL5 depletion decreases pre‐mRNA splicing efficiency, leading to globally enhanced intron retention. Defective sister chromatid cohesion is a general consequence of dysfunctional pre‐mRNA splicing, resulting from the selective downregulation of the cohesion protection factor Sororin. As the UBL5 yeast orthologue, Hub1, also promotes spliceosome functions, our results show that UBL5 plays an evolutionary conserved role in pre‐mRNA splicing, the integrity of which is essential for the fidelity of chromosome segregation.
Murine Langerin+ dermal dendritic cells prime CD8+T cells while Langerhans cells induce cross‐tolerance
Authors: Flacher Vincent , Tripp Christoph H , Mairhofer David G , Steinman Ralph M , Stoitzner Patrizia , Idoyaga Juliana , Romani Nikolaus 
Published: August 2014

AbstractSkin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C‐type lectin Langerin/CD207 are cross‐presented to CD8+ T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin+ dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti‐CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)‐coupled anti‐Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin+ dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8+ T‐cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross‐presentation to CD8+ T cells. Langerin/OVA combined with imiquimod could not prime CD8+ T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin+ dDCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8+ T‐cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.
Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa
Authors: Pewzner‐Jung Yael , Tavakoli Tabazavareh Shaghayegh , Grassmé Heike , Becker Katrin Anne , Japtok Lukasz , Steinmann Jörg , Joseph Tammar , Lang Stephan , Tuemmler Burkhard , Schuchman Edward H , Lentsch Alex B , Kleuser Burkhard , Edwards Michael J , Futerman Anthony H , Gulbins Erich 
Published: August 2014

AbstractCystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P. aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P. aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection.