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It is known that Yersinia pestis kills Caenorhabditis elegans by a biofilm‐dependent mechanism that is similar to the mechanism used by the pathogen to block food intake in the flea vector. Using Y. pestis KIM5, which lacks the genes that are required for biofilm formation, we show that Y. pestis can kill C. elegans by a biofilm‐independent mechanism that correlates with the accumulation of the pathogen in the intestine. We used this novel Y. pestis–C. elegans pathogenesis system to show that previously known and unknown virulence‐related genes are required for full virulence in C. elegans. Six Y. pestis mutants with insertions in genes that are not related to virulence before were isolated using C. elegans. One of the six mutants carried an insertion in a novel virulence gene and showed significantly reduced virulence in a mouse model of Y. pestis pathogenesis. Our results indicate that the Y. pestis–C. elegans pathogenesis system that is described here can be used to ide.jpgy and study previously uncharacterized Y. pestis gene products required for virulence in mammalian systems.

Adoptive transfer of autologous T cells genetically engineered to express chimeric antigen receptors (CARs) has emerged as a promising approach for the treatment of cancer. To this end, we have been developing an anti-BMCA CAR T cell approach for the potential treatment of multiple myeloma. B cell maturation antigen (BCMA) is an attractive CAR T cell target since nearly all multiple myeloma tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. However, to fully realize the therapeutic potential of these engineered T cells will require the development of simple and robust manufacturing processes capable of supporting larger clinical studies as well as the scale up to commercial cell product generation.bluebird bio's approach has focused on developing a simple and robust closed system manufacturing process that could be readily transferrable to cGMP manufacturing. Briefly, cultures are initiated with autologous PBMC in the presence of anti-CD3 and anti-CD28 antibodies obviating the need for T cell selection. Activated T cells are then efficiently transduced with an anti-BCMA Lentiviral vector by direct inoculation of the culture with the virus. The T cells are then expanded for a relatively short period of 7-10 days in gas permeable culture bags. Finally, cells are harvested, washed and cryopreserved in the final formulation for infusion.Using the above clinical manufacturing platform, we consistently achieve greater than 6 population doublings in 7-10 days, starting with as little as 100e6 PBMC. Despite using PBMC as input, the purity of the cell product after expansion is >99 % CD3+. Moreover, by using our experience in generating clinic ready high titer Lentiviral vectors we are able to consistently achieve >50 % of the T cells expressing the anti-BCMA CAR from a single round of transduction with an average vector copy number of 1.73 ± 0.43 Importantly, the anti-BCMA CAR T cells manufactured using the above platform retain potent anti-tumor activity both in vitro and in vivo.In summary, the Lentiviral-based CAR T cell manufacturing platform we have established is robust, and results in a high quality cell product. Importantly, this is achieved with fewer complex manipulations representing an important step toward the development of CAR T cell products.

It's Halloween time, and the ghosts and goblins of HEAL Utah are out to scare people once again. HEAL has suggested that EnergySolutions is out to sidestep the law by seeking a license amendment that allows for greater disposal capacity at its Clive facility. The truth is that EnergySolutions has always followed the legal and regulatory path prescribed by the state of Utah and will continue to do so in the future. Here's the issue. EnergySolutions would like to combine two disposal cells into one cell on its licensed facility, known as Section 32. The engineering and design for the new cell has already been evaluated by a third party consultant and approved by the State of Utah Division of Radiation Control.

If Mr. [Jim Matheson] wants to level the playing field, I have an idea. Let's have both [Doug Wright] and Jim resign from their day jobs. If Mr. Matheson is concerned about someone having an unfair advantage, it only stands to reason that he would be willing to resign from his seat in Congress and give up all of its attendant perks. Give up the taxpayer-funded mailing privileges (Matheson has spent hundreds of thousands of taxpayer dollars in free constituent mailings since taking office), give up his taxpayer funded PR machine that concocted the idea of the letter to KSL and then leaked it to the media, and give up the fund-raising advantage that incumbents have to raise millions of dollars in special interest money. Then we might have a fair fight on our hands.

Background and objective Gastroesophageal reflux disease (GORD) is highly prevalent in idiopathic pulmonary fibrosis (IPF) and may play a role in its pathogenesis. Recent IPF treatment guidelines suggest that all patients with IPF be considered for antacid therapy. However, emerging evidence suggests that antacid therapy does not improve IPF patient outcomes and may increase the risk of pulmonary infection. Methods Using prospectively collected data from the Australian IPF Registry including use of antacid therapy, GORD diagnosis and GORD symptoms, the relationship of these GORD variables to survival and disease progression was assessed. The severity of GORD symptoms using the frequency scale for symptoms of GORD (FSSG) and its relationships to outcomes was also assessed for the first time in an IPF cohort. Results Five hundred eighty-seven (86%) of the 684 patients in the Australian IPF Registry were eligible for inclusion. Patients were mostly male (69%), aged 71.0 ± 8.5 years with moderate disease (FVC 81.7 ± 21.5%; DLco 48.5 ± 16.4%). Most patients were taking antacids ( n  = 384; 65%), though fewer had a diagnosis of GORD ( n  = 243, 41.4%) and typical GORD symptoms were even less common ( n  = 171, 29.1%). The mean FSSG score was 8.39 ± 7.45 with 43% ( n  = 251) having a score > 8. Overall, there was no difference in survival or disease progression, regardless of antacid treatment, GORD diagnosis or GORD symptoms. Conclusions Neither the use of antacid therapy nor the presence of GORD symptoms affects longer term outcomes in IPF patients. This contributes to the increasing evidence that antacid therapy may not be beneficial in IPF patients and that GORD directed therapy should be considered on an individual basis to treat the symptoms of reflux.

Epidemiological studies show that approximately 20-30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10-15% develop lung cancer. COPD pre-exists lung cancer in 50-90% of cases and has a heritability of 40-77%, much greater than for lung cancer with heritability of 15-25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV(1), appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1) is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the \"risk genotypes\" derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.

This resource covers basic concepts and modeling examples for the three “pillars” of EW: Electronic Attack (EA) systems, Electronic Protection (EP) techniques, and Electronic Support (ES). It develops techniques for the modeling and simulation (M&S) of modern radar and electronic warfare (EW) systems and reviews radar principles, including the radar equation. M&S techniques are introduced, and example models developed in MATLAB and Simulink are presented and discussed in detail. These individual models are combined to create a full end-to-end engineering engagement simulation between a pulse-Doppler radar and a target. The radar-target engagement model is extended to include jamming models and is used to illustrate the interaction between radar and jamming signals and the impact on radar detection and tracking. In addition, several classic EA techniques are introduced and modeled, and the effects on radar performance are explored. This book is a valuable resource for engineers, scientists, and managers who are involved in the design, development, or testing of radar and EW systems. It provides a comprehensive overview of the M&S techniques that are used in these systems, and the book's many examples and case studies provide a solid foundation for understanding how these techniques can be applied in practice.

In 1942 Waddington observed that phenotype variation among mutant animals is greater than in wild types. Here we update this observation to depict unexpected relationships between phenotype severity and variation. Using a zebrafish mef2ca allelic series representing a range in craniofacial phenotype severity, we tested the straightforward hypothesis that as phenotype severity increases, variation increases. We found that severity and variation were positively correlated, but only to a point. Variation collapsed in the most severe conditions. Mathematically, we found that the best fit for the relationship between severity and variation is a quadratic function. Across both zebrafish craniofacial phenotypes and human genetic disease, wild-type conditions produced low variation, moderate severity was associated with high variation, and conditions of extreme severity resulted in low variation. We propose that the quadratic relationship between severity and variation is a universal principle of biology that until now has not been formally tested. Phenotype variation is higher in mutants than wild types. Examining a range of mutant severities, this study unexpectedly found that variation decreases in severe conditions. A quadratic trend best fits the relationship between severity and variation.

The pipeline embolization device (PED) is the latest technology available for intracranial aneurysm treatment. To report early postmarket results with the PED. This study was a prospective registry of patients treated with PEDs at 7 American neurosurgical centers subsequent to Food and Drug Administration approval of this device. Data collected included clinical presentation, aneurysm characteristics, treatment details, and periprocedural events. Follow-up data included degree of aneurysm occlusion and delayed (> 30 days after the procedure) complications. Sixty-two PED procedures were performed to treat 58 aneurysms in 56 patients. Thirty-seven of the aneurysms (64%) treated were located from the cavernous to the superior hypophyseal artery segment of the internal carotid artery; 22% were distal to that segment, and 14% were in the vertebrobasilar system. A total of 123 PEDs were deployed with an average of 2 implanted per aneurysm treated. Six devices were incompletely deployed; in these cases, rescue balloon angioplasty was required. Six periprocedural (during the procedure/within 30 days after the procedure) thromboembolic events occurred, of which 5 were in patients with vertebrobasilar aneurysms. There were 4 fatal postprocedural hemorrhages (from 2 giant basilar trunk and 2 large ophthalmic artery aneurysms). The major complication rate (permanent disability/death resulting from perioperative/delayed complication) was 8.5%. Among 19 patients with 3-month follow-up angiography, 68% (13 patients) had complete aneurysm occlusion. Two patients presented with delayed flow-limiting in-stent stenosis that was successfully treated with angioplasty. Unlike conventional coil embolization, aneurysm occlusion with PED is not immediate. Early complications include both thromboembolic and hemorrhagic events and appear to be significantly more frequent in association with treatment of vertebrobasilar aneurysms.

Context Many arboreal mammals in Neotropical forests are important seed dispersers that influence the spatial patterns of tree regeneration via their movement patterns, which in turn are determined by the canopy structure of the forest itself. However, the relationship between arboreal mammal movement and canopy structure is poorly understood, due in large part to the complexity of quantifying arboreal habitat structure. Objectives We relate detailed movement trajectories of three sympatric primate species to attributes of canopy structure derived from airborne light detection and ranging (LiDAR) in order to understand the role of structure in arboreal movement in the tropical moist forest of Barro Colorado Island, Panama. Methods We used high-resolution LiDAR to quantify three-dimensional attributes of the forest canopy of the entire island, high-resolution GPS tracking to map the movement patterns of the monkey species, and step selection functions to relate movement decisions to canopy attributes. Results We found that movement decisions were correlated with canopy height and distance to gaps, which indicate forest maturity and lateral connectivity, in all three species. In the two faster-moving species, step selection was also correlated with the thickness of the crown layer and the density of vegetation within the crown. Conclusions The correlations detected are fully in line with known differences in the locomotor adaptations and movement strategies of the study species, and directly reflect maximization of energetic efficiency and ability to escape from predators. Quantification of step selection in relation to structure thus provides insight into the ways in which arboreal animals use their environment.