Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction

Double Non-Global Logarithms In-N-Out of Jets

We derive the leading non-global logarithms (NGLs) of ratios of jet masses m_{1,2} and a jet energy veto \Lambda due to soft gluons splitting into regions in and out of jets. Such NGLs appear in any exclusive jet cross section with multiple jet measurements or with a veto imposed on additional jets. Here, we consider back-to-back jets of radius R produced in e^+e^- collisions, found with a cone or recombination algorithm. The leading NGLs are of the form \alpha_s^2 \ln^2(\Lambda/m_{1,2}) or \alpha_s^2\ln^2(m_1/m_2). Their coefficients depend both on the algorithm and on R. We consider cone, \kt, anti-\kt, and Cambridge-Aachen algorithms. In addition to determining the full algorithmic and R dependence of the leading NGLs, we derive new relations among their coefficients. We also derive to all orders in \alpha_s a factorized form for the soft function S(k_L,k_R,\Lambda) in the cross section \sigma(m_1,m_2,\Lambda) in which dependence on each of the global logs of \mu/k_L, \mu/k_R and \mu/\Lambda determined by the renormalization group are separated from one another and from the non-global logs. The same kind of soft function, its associated non-global structure, and the algorithmic dependence we derive here will also arise in exclusive jet cross sections at hadron colliders, and must be understood and brought under control to achieve precise theoretical predictions.Comment: 19 pages, 10 figures. v2: minor edits, additional discussion in Introduction. v3: version published in JHE

Jet Shapes and Jet Algorithms in SCET

Jet shapes are weighted sums over the four-momenta of the constituents of a jet and reveal details of its internal structure, potentially allowing discrimination of its partonic origin. In this work we make predictions for quark and gluon jet shape distributions in N-jet final states in e+e- collisions, defined with a cone or recombination algorithm, where we measure some jet shape observable on a subset of these jets. Using the framework of Soft-Collinear Effective Theory, we prove a factorization theorem for jet shape distributions and demonstrate the consistent renormalization-group running of the functions in the factorization theorem for any number of measured and unmeasured jets, any number of quark and gluon jets, and any angular size R of the jets, as long as R is much smaller than the angular separation between jets. We calculate the jet and soft functions for angularity jet shapes \tau_a to one-loop order (O(alpha_s)) and resum a subset of the large logarithms of \tau_a needed for next-to-leading logarithmic (NLL) accuracy for both cone and kT-type jets. We compare our predictions for the resummed \tau_a distribution of a quark or a gluon jet produced in a 3-jet final state in e+e- annihilation to the output of a Monte Carlo event generator and find that the dependence on a and R is very similar.Comment: 62 pages plus 21 pages of Appendices, 13 figures, uses JHEP3.cls. v2: corrections to finite parts of NLO jet functions, minor changes to plots, clarified discussion of power corrections. v3: Journal version. Introductory sections significantly reorganized for clarity, classification of logarithmic accuracy clarified, results for non-Mercedes-Benz configurations adde

Pseudorabies Virus Infected Porcine Epithelial Cell Line Generates a Diverse Set of Host MicroRNAs and a Special Cluster of Viral MicroRNAs

Pseudorabies virus (PRV) belongs to Alphaherpesvirinae subfamily that causes huge economic loss in pig industry worldwide. It has been recently demonstrated that many herpesviruses encode microRNAs (miRNAs), which play crucial roles in viral life cycle. However, the knowledge about PRV-encoded miRNAs is still limited. Here, we report a comprehensive analysis of both viral and host miRNA expression profiles in PRV-infected porcine epithelial cell line (PK-15). Deep sequencing data showed that the ∼4.6 kb intron of the large latency transcript (LLT) functions as a primary microRNA precursor (pri-miRNA) that encodes a cluster of 11 distinct miRNAs in the PRV genome, and 209 known and 39 novel porcine miRNAs were detected. Viral miRNAs were further confirmed by stem-loop RT-PCR and northern blot analysis. Intriguingly, all of these viral miRNAs exhibited terminal heterogeneity both at the 5′ and 3′ ends. Seven miRNA genes produced mature miRNAs from both arms and two of the viral miRNA genes showed partially overlapped in their precursor regions. Unexpectedly, a terminal loop-derived small RNA with high abundance and one special miRNA offset RNA (moRNA) were processed from a same viral miRNA precursor. The polymorphisms of viral miRNAs shed light on the complexity of host miRNA-processing machinery and viral miRNA-regulatory mechanism. The swine genes and PRV genes were collected for target prediction of the viral miRNAs, revealing a complex network formed by both host and viral genes. GO enrichment analysis of host target genes suggests that PRV miRNAs are involved in complex cellular pathways including cell death, immune system process, metabolic pathway, indicating that these miRNAs play significant roles in virus-cells interaction of PRV and its hosts. Collectively, these data suggest that PRV infected epithelial cell line generates a diverse set of host miRNAs and a special cluster of viral miRNAs, which might facilitate PRV replication in cells

Allele-Specific Gene Expression Is Widespread Across the Genome and Biological Processes

Allelic specific gene expression (ASGE) appears to be an important factor in human phenotypic variability and as a consequence, for the development of complex traits and diseases. In order to study ASGE across the human genome, we have performed a study in which genotyping was coupled with an analysis of ASGE by screening 11,500 SNPs using the Mapping 10 K Array to identify differential allelic expression. We found that from the 5,133 SNPs that were suitable for analysis (heterozygous in our sample and expressed in peripheral blood mononuclear cells), 2,934 (57%) SNPs had differential allelic expression. Such SNPs were equally distributed along human chromosomes and biological processes. We validated the presence or absence of ASGE in 18 out 20 SNPs (90%) randomly selected by real time PCR in 48 human subjects. In addition, we observed that SNPs close to -but not included in- segmental duplications had increased levels of ASGE. Finally, we found that transcripts of unknown function or non-coding RNAs, also display ASGE: from a total of 2,308 intronic SNPs, 1510 (65%) SNPs underwent differential allelic expression. In summary, ASGE is a widespread mechanism in the human genome whose regulation seems to be far more complex than expected

Wild Type and Mutant 2009 Pandemic Influenza A (H1N1) Viruses Cause More Severe Disease and Higher Mortality in Pregnant BALB/c Mice

BACKGROUND: Pregnant women infected by the pandemic influenza A (H1N1) 2009 virus had more severe disease and higher mortality but its pathogenesis is still unclear. PRINCIPAL FINDINGS: We showed that higher mortality, more severe pneumonitis, higher pulmonary viral load, lower peripheral blood T lymphocytes and antibody responses, higher levels of proinflammatory cytokines and chemokines, and worse fetal development occurred in pregnant mice than non-pregnant controls infected by either wild type (clinical isolate) or mouse-adapted mutant virus with D222G substitution in hemagglutinin. These disease-associated changes and the lower respiratory tract involvement were worse in pregnant mice challenged by mutant virus. Though human placental origin JEG-3 cell line could be infected and proinflammatory cytokines or chemokines were elevated in amniotic fluid of some mice, no placental or fetal involvement by virus were detected by culture, real-time reverse transcription polymerase chain reaction or histopathological changes. Dual immunofluorescent staining of viral nucleoprotein and type II alveolar cell marker SP-C protein suggested that the majority of infected alveolar epithelial cells were type II pneumocytes. CONCLUSION: The adverse effect of this pandemic virus on maternal and fetal outcome is largely related to the severe pulmonary disease and the indirect effect of inflammatory cytokine spillover into the systemic circulation

Structural Comparison of Human Mammalian Ste20-Like Kinases

BACKGROUND: The serine/threonine mammalian Ste-20 like kinases (MSTs) are key regulators of apoptosis, cellular proliferation as well as polarization. Deregulation of MSTs has been associated with disease progression in prostate and colorectal cancer. The four human MSTs are regulated differently by C-terminal regions flanking the catalytic domains. PRINCIPAL FINDINGS: We have determined the crystal structure of kinase domain of MST4 in complex with an ATP-mimetic inhibitor. This is the first structure of an inactive conformation of a member of the MST kinase family. Comparison with active structures of MST3 and MST1 revealed a dimeric association of MST4 suggesting an activation loop exchanged mechanism of MST4 auto-activation. Together with a homology model of MST2 we provide a comparative analysis of the kinase domains for all four members of the human MST family. SIGNIFICANCE: The comparative analysis identified new structural features in the MST ATP binding pocket and has also defined the mechanism for autophosphorylation. Both structural features may be further explored for inhibitors design. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

The Arabidopsis leucine-rich repeat receptor kinase MIK2/LRR-KISS connects cell wall integrity sensing, root growth and response to abiotic and biotic stresses

Plants actively perceive and respond to perturbations in their cell walls which arise during growth, biotic and abiotic stresses. However, few components involved in plant cell wall integrity sensing have been described to date. Using a reverse-genetic approach, we identified the Arabidopsis thaliana leucine-rich repeat receptor kinase MIK2 as an important regulator of cell wall damage responses triggered upon cellulose biosynthesis inhibition. Indeed, loss-of-function mik2 alleles are strongly affected in immune marker gene expression, jasmonic acid production and lignin deposition. MIK2 has both overlapping and distinct functions with THE1, a malectin-like receptor kinase previously proposed as cell wall integrity sensor. In addition, mik2 mutant plants exhibit enhanced leftward root skewing when grown on vertical plates. Notably, natural variation in MIK2 (also named LRR-KISS) has been correlated recently to mild salt stress tolerance, which we could confirm using our insertional alleles. Strikingly, both the increased root skewing and salt stress sensitivity phenotypes observed in the mik2 mutant are dependent on THE1. Finally, we found that MIK2 is required for resistance to the fungal root pathogen Fusarium oxysporum. Together, our data identify MIK2 as a novel component in cell wall integrity sensing and suggest that MIK2 is a nexus linking cell wall integrity sensing to growth and environmental cues

Identification of neural networks that contribute to motion sickness through principal components analysis of fos labeling induced by galvanic vestibular stimulation

Motion sickness is a complex condition that includes both overt signs (e.g., vomiting) and more covert symptoms (e.g., anxiety and foreboding). The neural pathways that mediate these signs and symptoms are yet to identified. This study mapped the distribution of c-fos protein (Fos)-like immunoreactivity elicited during a galvanic vestibular stimulation paradigm that is known to induce motion sickness in felines. A principal components analysis was used to identify networks of neurons activated during this stimulus paradigm from functional correlations between Fos labeling in different nuclei. This analysis identified five principal components (neural networks) that accounted for greater than 95% of the variance in Fos labeling. Two of the components were correlated with the severity of motion sickness symptoms, and likely participated in generating the overt signs of the condition. One of these networks included neurons in locus coeruleus, medial, inferior and lateral vestibular nuclei, lateral nucleus tractus solitarius, medial parabrachial nucleus and periaqueductal gray. The second included neurons in the superior vestibular nucleus, precerebellar nuclei, periaqueductal gray, and parabrachial nuclei, with weaker associations of raphe nuclei. Three additional components (networks) were also identified that were not correlated with the severity of motion sickness symptoms. These networks likely mediated the covert aspects of motion sickness, such as affective components. The identification of five statistically independent component networks associated with the development of motion sickness provides an opportunity to consider, in network activation dimensions, the complex progression of signs and symptoms that are precipitated in provocative environments. Similar methodology can be used to parse the neural networks that mediate other complex responses to environmental stimuli. © 2014 Balaban et al

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability