Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies

Gene regulatory networks elucidating huanglongbing disease mechanisms.

Next-generation sequencing was exploited to gain deeper insight into the response to infection by Candidatus liberibacter asiaticus (CaLas), especially the immune disregulation and metabolic dysfunction caused by source-sink disruption. Previous fruit transcriptome data were compared with additional RNA-Seq data in three tissues: immature fruit, and young and mature leaves. Four categories of orchard trees were studied: symptomatic, asymptomatic, apparently healthy, and healthy. Principal component analysis found distinct expression patterns between immature and mature fruits and leaf samples for all four categories of trees. A predicted protein - protein interaction network identified HLB-regulated genes for sugar transporters playing key roles in the overall plant responses. Gene set and pathway enrichment analyses highlight the role of sucrose and starch metabolism in disease symptom development in all tissues. HLB-regulated genes (glucose-phosphate-transporter, invertase, starch-related genes) would likely determine the source-sink relationship disruption. In infected leaves, transcriptomic changes were observed for light reactions genes (downregulation), sucrose metabolism (upregulation), and starch biosynthesis (upregulation). In parallel, symptomatic fruits over-expressed genes involved in photosynthesis, sucrose and raffinose metabolism, and downregulated starch biosynthesis. We visualized gene networks between tissues inducing a source-sink shift. CaLas alters the hormone crosstalk, resulting in weak and ineffective tissue-specific plant immune responses necessary for bacterial clearance. Accordingly, expression of WRKYs (including WRKY70) was higher in fruits than in leaves. Systemic acquired responses were inadequately activated in young leaves, generally considered the sites where most new infections occur

Supersymmetry Without Prejudice at the 7 TeV LHC

We investigate the model independent nature of the Supersymmetry search strategies at the 7 TeV LHC. To this end, we study the missing-transverse-energy-based searches developed by the ATLAS Collaboration that were essentially designed for mSUGRA. We simulate the signals for ~71k models in the 19-dimensional parameter space of the pMSSM. These models have been found to satisfy existing experimental and theoretical constraints and provide insight into general features of the MSSM without reference to a particular SUSY breaking scenario or any other assumptions at the GUT scale. Using backgrounds generated by ATLAS, we find that imprecise knowledge of these estimated backgrounds is a limiting factor in the potential discovery of these models and that some channels become systematics-limited at larger luminosities. As this systematic error is varied between 20-100%, roughly half to 90% of this model sample is observable with significance S>5 for 1 fb^{-1} of integrated luminosity. We then examine the model characteristics for the cases which cannot be discovered and find several contributing factors. We find that a blanket statement that squarks and gluinos are excluded with masses below a specific value cannot be made. We next explore possible modifications to the kinematic cuts in these analyses that may improve the pMSSM model coverage. Lastly, we examine the implications of a null search at the 7 TeV LHC in terms of the degree of fine-tuning that would be present in this model set and for sparticle production at the 500 GeV and 1 TeV Linear Collider.Comment: 51 pages, 26 figure

Paired-domination in inflated graphs

2003-2004 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe

Accretion, Primordial Black Holes and Standard Cosmology

Primordial Black Holes evaporate due to Hawking radiation. We find that the evaporation time of primordial black holes increase when accretion of radiation is included.Thus depending on accretion efficiency more and more number of primordial black holes are existing today, which strengthens the idea that the primordial black holes are the proper candidate for dark matter.Comment: 11 pages, 3 figure

Transient Expression of Tetrameric Recombinant Human Butyrylcholinesterase in Nicotiana benthamiana.

To optimize the expression, extraction and purification of plant-derived tetrameric recombinant human butyrylcholinesterase (prBChE), we describe the development and use of plant viral amplicon-based gene expression system; Tobacco Mosaic Virus (TMV) RNA-based overexpression vector (TRBO) to express enzymatically active FLAG-tagged plant made recombinant butyrylcholinesterase (rBChE) in Nicotiana benthamiana leaves using transient agroinfiltration. Two gene expression cassettes were designed to express the recombinant protein in either the ER or to the apoplastic compartment. Leaf homogenization was used to isolate ER-retained recombinant butyrylcholinesterase (prBChE-ER) while apoplast-targeted rBChE was isolated by either leaf homogenization (prBChE) or vacuum-extraction of apoplastic wash fluid (prBChE-AWF). rBChE from apoplast wash fluid had a higher specific activity but lower enzyme yield than leaf homogenate. To optimize the isolation and purification of total recombinant protein from leaf homogenates, an acidic extraction buffer was used. The acidic extraction buffer yielded >95% enzymatically active tetrameric rBChE as verified by Coomassie stained and native gel electrophoresis. Furthermore, when compared to human butyrylcholinesterase, the prBChE was found to be similar in terms of tetramerization and enzyme kinetics. The N-linked glycan profile of purified prBChE-ER was found to be mostly high mannose structures while the N-linked glycans on prBChE-AWF were primarily complex. The glycan profile of the prBChE leaf homogenates showed a mixture of high mannose, complex and paucimannose type N-glycans. These findings demonstrate the ability of plants to produce rBChE that is enzymatically active and whose oligomeric state is comparable to mammalian butyrylcholinesterase. The process of plant made rBChE tetramerization and strategies for improving its pharmacokinetics properties are also discussed

Green Vehicle Routing Optimization Based on Carbon Emission and Multiobjective Hybrid Quantum Immune Algorithm

© 2018 Xiao-Hong Liu et al. Green Vehicle Routing Optimization Problem (GVROP) is currently a scientific research problem that takes into account the environmental impact and resource efficiency. Therefore, the optimal allocation of resources and the carbon emission in GVROP are becoming more and more important. In order to improve the delivery efficiency and reduce the cost of distribution requirements through intelligent optimization method, a novel multiobjective hybrid quantum immune algorithm based on cloud model (C-HQIA) is put forward. Simultaneously, the computational results have proved that the C-HQIA is an efficient algorithm for the GVROP. We also found that the parameter optimization of the C-HQIA is related to the types of artificial intelligence algorithms. Consequently, the GVROP and the C-HQIA have important theoretical and practical significance