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Matrix metalloproteinases (MMPs) are a family of at least 20 enzymes that are traditionally noted for their ability to degrade all components of the extracellular matrix, thereby, assigning them critical roles in connective tissue remodeling in normal physiology and in disease pathology (Reviewed in Brinckerhoff and Matrisian, 2002; Vincenti and Brinckerhoff, 2007). While levels of MMPs are usually low during homeostasis, conventional wisdom holds that their overexpression and dysregulation in many diseases, including cancer, account for their prominent role in disease progression. In contrast, the current paper by Pallavalli et al. (2009) postulates the exact opposite that over-expression of a specific MMP is actually protective against aggressive melanoma. The authors carried out mutational analyses of eight MMP genes in melanomas from 32 patients, and identified 28 somatic mutations. They found that MMP-8, a collagenase, was one of the most commonly mutated genes, and identified five distinct mutations. Importantly, these mutated forms of MMP-8 exhibited reduced collagenolytic activity, but cells expressing mutant MMP-8 showed increases in tumor growth on soft agar in vitro and in tumor formation in vivo, compared to cells with wild type MMP-8. Thus, mutant MMP-8 is associated with aggressive melanoma, leading the authors to conclude that wild-type MMP-8 is protective against invasive melanoma, and may function as a tumor suppressor gene. The notion that MMPs have important functions unrelated to matrix degradation is not new (Brinckerhoff and Matrisian, 2002; Vincenti and Brinckerhoff, 2007). They contribute to crucial events in disease pathology, such as cell proliferation, differentiation, apoptosis, and angiogenesis, thereby illustrating their ability to modulate a multitude of cell behaviors. In addition, it is well recognized that some level of MMP activity is essential for normal physiology, and knocking out a particular MMP in mice has demonstrated that the complete absence of a certain MMP can be associated with an unfavorable phenotype (Vincenti and Brinckerhoff, 2007). In keeping with the present study, knock out of MMP-8 in mice was associated with increased skin tumor susceptibility and with enhanced metastasis of melanoma (Gutierrez-Fernandez et al., 2008; Vincenti and Brinckerhoff, 2007). In the skin tumor model, the MMP-8 null mice displayed decreased inflammation suggesting that MMPs may have a protective role vis-a-vis the immune ⁄ inflammatory responses. In the melanoma model, tumor cells expressing wild-type MMP-8 showed increased adhesion to matrix proteins, which was absent in cells expressing mutant MMP-8. From this, the authors conclude that MMP-8 potentiates cell adhesion, which may explain how this proteinase reduces cell invasion (Gutierrez-Fernandez et al., 2008). Interestingly, the authors also hint at a possible role for MMP-8 in an intact immune system, claiming that secretion of MMP-8 by tumor-infiltrating neutrophils in wild type (versus MMP-8 null) mice could contribute to reduced tumor dissemination (Gutierrez-Fernandez et al., 2008). Thus, the findings that expression of a mutant, non-collagenolytic protein in human melanomas is associated with increased tumor growth in vitro and increased tumor formation in vivo confirm the prior experimental results in mice. They are, therefore, not totally surprising. However, their observations take several important steps forward by extending the experimental studies to actual patient samples, and by documenting numerous mutations in the coding region of human MMP-8 isolated from melanomas. Their data are extensive and compelling, clearly showing by over expressing mutant protein and knocking down wild-type, that wild-type protein is protective and that mutant is linked to melanoma progression. The concept of proteinases functioning as tumor suppressors has been suggested previously (Lopez-Otin and Matrisian, 2007). Nonetheless, Palavalli et al. now formally propose that MMP-8 functions as a tumor suppressor gene. Their claim is supported by two salient observations: (1) in seven tumors, both alleles of MMP-8 were affected, while other mutations in the gene were accompanied by loss of heterozygosity, both of which are characteristics associated with tumor suppressor genes, and (2) there was a higher than expected ratio of non-synonymous to synonymous somatic mutations suggesting that they are ‘driver mutations,’ which are dominant. Thus, ‘tumor suppressor’ may be an important function that can be added to the repertoire of activities associated with at least one MMP family member. The mutations in MMP-8 were found in the proteglycan-binding and catalytic domains, and both abrogated collagenolytic activity. Furthermore, as cells expressing mutant MMP-8 were more aggressive, it follows that this aggressive behavior is unrelated to the ability of MMP-8 to degrade collagen. However, the mechanism(s) by which MMP-8 exerts its putative tumor suppressive effects is unclear. The suggestion that MMP-8 null mice have compromised immune ⁄ inflammatory responses raises the possibility that this mechanism is operational here. The fact that severely immuno-compromised NOD ⁄SCID mice were used in the in vivo experiments with human melanomas may preclude assessment of effects of the immune system. This contrasts with studies in the MMP-8 null mice, which harbor an intact immune system, with the exception of no MMP-8 expression by the host cells (Gutierrez-Fernandez et al., 2008). Thus, in keeping with previous studies that implicate a protective effect of MMPs on the immune ⁄ inflammatory responses, this remains an intriguing, and reasonably likely, possibility for MMP-8 in human melanoma. A corollary to this concept is the importance of tumor–host cell interactions, and their influence on the tumor microenvironment. This corollary has raised the possibility that wild-type MMP-8 has novel function(s) in suppressing melanoma. It has *Yogi Berra Coverage on: Palavalli, L.H., Prickett, T.D., Wunderlich, J.R., Wei, X., et al. (2009). Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat. Genet. Advanced onlinepublication,doi:10.1038/ng.340.

Some applications are reported of a recent procedure developed by Young for crack growth, which calculates three dimensional stress intensity factors by boundary integral equations. These are used to compute fatigue crack growth as cracks grow. The present paper applies the method to a fully through crack of uniform size initially at the centre of a block under uniform tension. Further analyses were then carried out for cases when there are two further initially circular cracks in a plane parallel to that of the through crack. The calculations showed that when the distance between the planes was equal to the initial radius of the circular crack the cracks attracted each other without intersecting, but intersection occurred when the spacing was half this amount.

Contemporary competitive demands have forced many organizations to increase levels of flexibility and adaptability in their operations. A growing number of such organizations have explored the virtual environment as one means of achieving increased responsiveness. In particular, the use of virtual teams appears to be on the increase. However, the increased use of virtual teams has not been accompanied by concomitant research efforts to understand better the social- psychological contributors to effective virtual teams. In this paper, we use a model of group effectiveness to propose a possible research agenda examining sources of virtual team effectiveness. Although much of this model offers insights relevant to the virtual environment, differences between groups and teams and between co- located and virtual environments suggest that modifications and additions to this model may be necessary. We offer a set of research propositions to advance future research on effective virtual teams beyond anecdote and description. Implications of this research agenda for managers of virtual teams and human resource pro- fessionals are also discussed.

The method of positron emission particle tracking (PEPT) has been adapted for use during extrusion. A particle 2 mm in diameter was tracked through a 45° conical die geometry using ram speeds of 5 and 10 mm min −1 . The particle was placed at different points across the diameter of the barrel in order to determine the dependence of the speed and strain rate on the initial position. Analysis of the speed of the particle during extrusion showed that the clay based paste used in the experiment exhibited plug flow in the barrel and the die land regions. The maximum extensional strain rate was shown to be independent of the ram speed, whereas the shear strain rate at the wall was highly dependent on the ram speed.

Dyeings (2% owf) were produced on conventional nylon 6.6 fabric using 1:2 metal-complex acid dyes. The fastness to the ISO 105:C06/C2 wash test over ten repetitions was determined. Aftertreatment of the dyeings using a commercial syntan improved the wash fastness over ten washes, and the sequential application of a cationic compound to the syntanned dyeings caused a further improvement.

We tested whether dispersal of juvenile lemmings occurs at high population densities and whether predation risk affects movements of juveniles. The study was conducted in July and August 1996 on the Kent Peninsula, Northwest Territories, during a peak in the lemming cycle. We fitted 43 juvenile collared lemmings (Dicrostonyx groenlandicus) of the summer generations on a control plot and a predator-exclosure plot with radio transmitters and examined their home ranges and movement patterns. We tested the following hypotheses: (i) extensive juvenile dispersal will occur at high population densities, (ii) male juveniles will move greater distances than females, and (iii) juveniles will move greater distances in the absence of predators. We rejected all these hypotheses. All juvenile collared lemmings remained in the vicinity of their original home ranges. Home-range sizes of all juveniles were similar, the mean size being 100 m2. Mean and maximum distances moved were similar among all juveniles. However, juveniles moved less frequently on the control plot than on the exclosure plot. Juvenile collared lemmings do not disperse at high densities. The lack of dispersal may have been the result of avoidance of confrontations with other lemmings, and may also have been related to delayed breeding, since most juveniles and subadults did not mature in late summer. Differential predation risk or predation mortality may have had no effect on the distances moved by juveniles or may have been masked by strong density effects on both plots.

To assist in the selection students for a baccalaureate program, a school of nursing instituted a group interview process. An exploratory qualitative design was used to assess faculty, community nurse, and student perceptions of the process. Faculty, community nurses, and students who participated in interviews were asked to complete a five-item, open-ended survey. Data analysis revealed that they enjoyed the process and identified it as beneficial. A positive aspect included students' getting to present themselves as more than a GPA. The use of group interviews provides additional information for faculty who are challenged with selecting students for enrollment in programs of nursing.

The purpose of this quasi-experimental study was to evaluate the effectiveness of a cognitive-behavioral nursing intervention for women with rheumatoid arthritis (RA). Ninety adult women with RA participated in 1 of 14 nurse-led groups over an 18-month period. Personal coping resources, pain-coping behaviors, psychological well-being, and disease symptomatology were measured at four time periods. There were significant changes on all of the measures of personal coping resources (p < .001) and psychological well-being (p < .05), half of the pain-coping behaviors (p < .05), and one indicator of disease symptomatology (fatigue, p < .05) from pre- to postintervention. Furthermore, the positive changes brought about by the program were maintained over the 3-month follow-up period. The intervention may be adapted to benefit individuals with a variety of stressful medical conditions.

A model aqueous injection moulding paste was investigated by capillary rheology. The experimental work consisted of 26 pressure measurement on each of three capillaries to provide an extended shear rate from 0.5 to 150 s?. A power law model was found to be adequate for general prediction of the low curve. However, slip flow had to be taken into account to map the shape of the flow curve more accurately. The Hatzikiriakos method, which does not require the use of different diameter capillaries, was applied to measure slip flow and gave rational solutions. The flow curve was modelled using rheological parameters for shear flow and slip flow over the region of the flow curve for which they were valid. The adjusted model incorporating slip flow gave a better correlation with the experimental results.

Dyeings (2% owf) were produced on conventional and microfibre nylon 6. 6 fabrics using unsulphonated, monosulphonated and disulphonated 1:2 metal complex acid dyes. When subjected to the ISO 105:C06/C2 wash test, the wash fastness behaviour of the dyeings was related to the degree of sulphonation of the dyes. Aftertreatment of the dyeings using a commercial syntan improved the wash fastness of the dyeings whereas the sequential application of a cationic compound to the syntanned dyeings caused a further improvement in wash fastness.

By separating the matrix from the agglomerate it was possible to determine the nature of agglomerate breakdown during extrusion within a known geometry. Previous attempts at observing agglomerate breakdown have been unsuccessful at relating the properties of the paste to the properties of the agglomerate due to the indistinguishability of the paste and the agglomerates. By using well-characterized materials, it was found that the breakdown probabilities of the agglomerates during extrusion were independent of the position of the agglomerate. This indicated that as the shear strain rate was known to be highly position dependent, the agglomerate breakdown was shear strain rate independent. Following breakdown, the distributive mixing was observed to be position dependent.

The paper and pulp industry have been the main pollutant of Finnish water bodies, but extensive investments have been made into improving internal and external purification. Activated sludge plants have been the most common waste water treatment method, but they are sensitive to shock loading and toxicity and their capacity to remove poorly biodegradable or toxic substances is limited. In this study pre-ozonation was investigated in order to prevent process failure, to improve the purification efficiency and to increase the removal rate of aquatic toxicity of the waste water. The ozonation of the most toxic paper and pulp mill effluent stream, bleaching effluent with the ozone dose, 0.4 MgO3 mg CODCr−1, increased the biodegradability measured as BOD/COD ratio by converting COD to BOD. This resulted in an increase in overall treatment efficiencies of up to 91 % BOD removal, 85% COD removal, compared to 22–60% BOD and 47–62 % COD without pre-ozonation. Pre-ozonation also helped to prevent process failure ca...

The causes of the defects in injection-moulded ceramic bars during debinding and sintering were investigated using density and shrinkage measurements in combination with macroscopic observation. Differential shrinkage during sintering is the main cause of post-debinding defects. Particle shape, mould geometry and gate position have a large effect on this differential shrinkage, while the volumetric shrinkage is almost constant and the influences of moulding conditions are relatively small. Particles with plate-like morphology orientate during moulding and contribute markedly to defect formation during debinding and sintering.

MYC and NOTCH are major oncogenic drivers in T-cell Acute Lymphoblastic Leukemia (T-ALL), yet additional collaborating genetic lesions collaborate to induce frank malignancy. To identify these factors, a large-scale transgenic screen was completed where 28 amplified and over-expressed genes found in human T-ALL were assessed for accelerating leukemia onset in the zebrafish transgenic model. From this analysis, Thymocyte selection-associated HMG protein (TOX) synergized with both MYC and NOTCH to induce T-ALL. Here, we show that TOX is highly expressed in 95% of human primary and relapse T-ALL when compared with both normal T cells and B-ALL. TOX is highly and specifically expressed in human T-ALL due to both genomic amplification and transcriptional regulation by the master transcription factors MYB/LMO2. Characterization of zebrafish T-ALLs revealed that TOX promoted genomic instability as assessed by changes in DNA content and Whole Genome Sequencing. Effects on genomic instability were confirmed by metaphase spread following TOX expression in MEF cells, confirming roles for TOX in regulating genomic instability and elevated DNA translocation potential in a wider range of cell types. To identify TOX binding partners, Tandem Mass Spectrometry was performed in human T-ALL cells. TOX was found to interact with KU70/KU80 but not other DNA repair enzymes, a result verified by co-immunoprecipitation studies. Given that TOX elevated genomic instability in the zebrafish model, that Ku70 or Ku80 loss lead to genomic instability and T cell lymphoma in mice, and that TOX bound specifically to KU70/KU80 - the initiating factors required for Non-Homologous End Joining (NHEJ) repair - we hypothesized that TOX is a negative regulator of double-strand break repair. Fluorescent repair assays were completed in 3T3 fibroblasts and confirmed that TOX inhibits NHEJ. Dynamic real-time imaging studies showed that TOX suppresses recruitment of fluorescent-tagged KU80 to DNA breaks. Importantly, TOX loss of function increased NHEJ in human T-ALL cells and reduced time to DNA repair as assessed by fluorescent Traffic Light Reporter assays and quantitative assessment of 53BP1 and γH2A.X foci resolution following irradiation. Our results show that TOX is aberrantly re-activated in 95% of human T-ALL, thereby suppressing KU70/KU80 function to promote genomic instability and ultimately elevating rates at which acquired mutations and rearrangements are amassed in developing pre-malignant T cells. Our work shows that TOX is the major oncogenic driver of genomic instability human T-ALL and locks cells in a constant state of dampened repair. Citation Format: Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Jessica Blackburn, Brian J. Abraham, Marc Mansour, Nouran S. Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon de Waard, Esha Jain, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B. Silverman, Ruslan Sadreyev, John Asara, A Thomas Look, Richard A. Young, Raul Mostoslavsky, Graham Dellaire, David M. Langenau. Thymocyte selection-associated HMG box protein (TOX) induces genomic instability in T-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3583.

Background Rheumatoid arthritis (RA) has a substantial negative impact on patients9 (pts) lives and is marked by pain and reduced mobility. In addition to RA articular manifestations, RA is often associated with important extra-articular manifestations, including anxiety and depression. 1 Objectives To describe pt self-reporting of anxiety and depression in pts with RA and to better characterize the association of anxiety/depression with disease activity, disability, and satisfaction with current treatment. Methods Descriptive analyses and multivariate linear and logistic regression analyses were performed using mood disorder data from the EU5 and US Adelphi RA Disease Specific Program. Presence of anxiety and depression was reported by pts that completed the EQ-5D anxiety/depression domain in the Patient Self Completion form. Multivariate models were run, controlling for pt age, gender, body mass index, and current disease severity, for each of the following measures: WPAI, HAQ-DI, DAS28 (ESR), and pt satisfaction with current treatment. WPAI, HAQ-DI, and DAS28 (ESR) data were evaluated using linear models, and pt-reported satisfaction were evaluated using logistic regression models. Results For the sample of pts included in the analysis (n=1,015), 38.4% of pts reported moderate or extreme anxiety/depression as their current health state. Pts with self-reported moderate (n=349) or extreme (n=41) anxiety/depression had greater work impairment, higher scores on the HAQ-DI, higher scores on the DAS28 (ESR), and a higher likelihood of being dissatisfied with their current treatment than those without stated depressed mood or anxiety. (n=625; Table). In multivariate analyses, significant differences were observed between the presence of pt-reported moderate anxiety/depression and higher WPAI scores ( P P P P =0.004), HAQ-DI ( P P =0.001), all compared to pts without anxiety or depression. Conclusions Anxiety and depression represent a significant burden for pts with RA. In this analysis, pt-reported mood disorders were independently associated with work impairment, disability, pt satisfaction with current treatment, and clinical disease activity. These findings highlight the multi-dimensional impact of anxiety and depression as a key extra-articular manifestation of RA. Further research on optimal management of this key unmet medical need is warranted. References Isik A, et al. Clin Rheumatol. 2007;26(6):872–878. Disclosure of Interest S. Peterson Shareholder of: Janssen, Employee of: Janssen, N. Li Employee of: Janssen, S. Blackburn Employee of: Adelphi Real World, D. Kielar Shareholder of: Janssen, Employee of: Janssen

Background Many patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA) do not receive advanced therapy (AT; a biologic or apremilast) or their first experience of AT is inadequate owing to lack of efficacy, intolerance or loss of benefit over time. Objectives To describe use of AT, treatment failure and switching, and assess implications of failure. Methods In this cross-sectional survey from five European countries and the USA, physicians with 3–30 years9 experience were eligible if currently treating patients with AS or PsA. Physician-completed record forms included reasons for switching AT, including “primary lack of efficacy (PLE, initial non-response)” and “secondary lack of efficacy (SLE, loss of response over time)”. Patients reported HRQoL (EQ-5D and SF-36), work productivity and activity impairment (WPAI) and HAQ-DI (PsA only). At analysis, current AT was assessed as “failed” if, after ≥3 months, disease severity had worsened since AT initiation or had remained severe, or if the physician was dissatisfied with disease control, perceived disease activity as “unstable” or “deteriorating”, or did not consider treatment a “success”. Results Data are presented from 599 physicians (457 EU/142 USA), 2018 patients with AS (1520/498) and 2436 with PsA (1839/597). Of 1889 AS patients with full treatment data, 33.5% had never received AT, 57.1% were receiving their first, 6.9% their second and 2.5% their third or later AT. Of the 2278 patients with PsA and full treatment data, the proportions were 40.8%, 48.0%, 7.9% and 3.2%, respectively. Of the 190 AS patients with known reasons for switching from first AT, 15.8% switched owing to PLE and 46.8% to SLE. Of the 245 PsA patients, the proportions were 22.0% and 44.9%. Despite PLE, patients continued on first-line AT for a mean 12.1 months (AS, n=30) and 9.5 months (PsA, n=52). The “failure” rate increased with successive ATs: 10.8% (116/1079) of AS patients on their first AT, 16.2% (21/130) on their second and 22.9% (11/48) on their third. For PsA, the rates were 11.0% (120/1094), 13.3% (24/181) and 19.2% (14/73). AS patients failing AT had significantly worse EQ-5D utilities (0.55 vs 0.82) and SF-36 physical component summary (PCS; 45.9 vs 73.3), mental component summary (MCS; 57.5 vs 69.6) and social function scale (SF; 53.8 vs 75.2) scores than those not failing (all p p p p =0.0024) and SF (60.4 vs 75.0, p p p =0.0112) and HAQ-DI (0.96 vs 0.55, p Conclusions This large multinational survey in AS and PsA showed that the main reason for switching AT is lack of efficacy. Failure of AT has significant negative effects on HRQoL and work productivity. Disclosure of Interest R. Alten Grant/research support from: Novartis, Speakers bureau: Novartis, V. Strand Consultant for: Abbvie, Amgen Corporation, AstraZeneca, BMS, Celgene, Celltrion, CORRONA, Genentech/Roche, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Lilly, Novartis, Pfizer, Regeneron, Sandoz, Sanofi and UCB, P. Conaghan Speakers bureau: Abbvie, Janssen, Lilly, Novartis, Pfizer and Roche, A. Deodhar Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer and UCB, Consultant for: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer and UCB, E. Sullivan Consultant for: Novartis, S. Blackburn Consultant for: Novartis, H. Tian Employee of: Novartis, K. Gandhi Shareholder of: Novartis, Employee of: Novartis, S. Jugl Shareholder of: Novartis, Employee of: Novartis

Background Many patients diagnosed with AS or PsA experience chronic fatigue or low energy which can persist during treatment and affect health related quality of life (HRQOL) and the ability to work. Objectives To assess self-reported fatigue in patients with AS and vitality in those with PsA, HRQOL and employment status. Methods In this fatigue and HRQOL study of a cross-sectional survey from 5 European countries and the USA, physicians with 3–30 years9 experience were eligible if treating patients with AS or PsA. Inclusion of patients was not restricted by treatment. Patients reported HRQOL (EQ-5D and SF-36), Work Productivity and Activity Impairment Questionnaire (WPAI) as well as other items. AS patients rated their fatigue using BASDAI (BASDAI-Fatigue). In PsA the SF-36 vitality domain (VT) was used to assess fatigue. Fatigue was classified in AS as non-severe (BASDAI-Fatigue 65 to 100), moderate (45 to 65) high (0 to Results Results are presented from 910 patients with AS (613 EU/297 USA) and 1136 with PsA (762/374) who completed questionnaires. Among AS patients who answered the BASDAI-Fatigue item, 42.0% [373/889] reported severe and 58.0% [516/889] non-severe fatigue. Tertiles of fatigue in PsA were defined based on responses from 1108 patients, who answered the SF-36 VT as: 33.6% [372/1108] low, 35.4% [392/1108] moderate and 31.0% [344/1108] high fatigue. AS patients reporting severe fatigue had significantly worse HRQOL than those with non-severe fatigue: EQ-5D utility (0.64 vs 0.89); SF-36 physical component summary (PCS) (52.7 vs 82.3); mental component summary (MCS) (54.4 vs 75.9) scores. All SF-36 domains were also significantly lower (all p PsA patients with high fatigue reported significantly worse HRQOL than those with low or moderate fatigue: EQ-5D (0.60 vs 0.93 and 0.81 respectively); SF-36 PCS (49.7 vs 90.2 vs. 74.1); SF-36 MCS (48.4 vs 84.4 vs. 67.3). All SF-36 domains were significantly worse, omitting VT as this was used for PsA fatigue classification. (all p Patients with AS reporting severe fatigue had significantly greater overall work impairment due to their disease than those with non-severe fatigue (WPAI (mean): 41.7% vs 13.7%; p Among 156 AS patients reporting additional information on retirement or unemployment, 98 had severe and 58 non-severe fatigue. Those with severe fatigue had significantly higher rates of retirement or unemployment due to AS (49.0% vs. 22.4%; p=0.0012). Conclusions This large analysis of patient-reported data shows that fatigue is common in AS and PsA with a substantial number reporting high/severe fatigue. Fatigue significantly affects HRQOL, social functioning, work productivity and therefore impacts patients9 daily life as well as societal costs. Disclosure of Interest P. Conaghan Speakers bureau: Abbvie, Janssen, Lilly, Novartis, Pfizer and Roche, A. Deodhar Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer and UCB, Consultant for: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer and UCB, V. Strand Consultant for: Abbvie, Amgen Corporation, AstraZeneca, BMS, Celgene, Celltrion, CORRONA, Genentech/Roche, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Lilly, Novartis, Pfizer, Regeneron, Sandoz, Sanofi and UCB, R. Alten Grant/research support from: Novartis, Speakers bureau: Novartis, E. Sullivan Consultant for: Novartis, S. Blackburn Consultant for: Novartis, H. Tian Employee of: Novartis, K. Gandhi Shareholder of: Novartis, Employee of: Novartis, S. Jugl Shareholder of: Novartis, Employee of: Novartis

The dual boundary element method has previously been used to analyse cracks in linear elastic materials in two dimensions and to evaluate the stress intensity factors by contour integrals around the crack tips. In this paper the method is extended to allow new cracks to initiate in response to the sudden increase in the loading coming from stress concentrations when existing cracks intersect with boundaries or with each other. The sensitivity and stability of the extended procedures are examined by their application to the investigation of the growth of cracks within a rectangular plate containing internal holes. The geometries studied consist of a single primary crack and various arrangements of one to five symmetrically placed circular holes; the plate is loaded by a uniform normal traction on its ends. The first test, on a single hole intersected by a primary crack, gives good agreement with previous results, while simulations with more holes show different regimes of crack initiation and growth in which various numbers of cracks initiate, in some cases linking the holes together.

Madder (Rubia tinctorum L.) has been used as a dye for over 2000 years with alizarin and purpurin the major natural dyes analysed from extractions undertaken. The use of ethanol as the solvent in the extraction process produced an extract that yielded four anthraquinone compounds lucidin primeveroside, ruberythric acid, alizarin and lucidin-ω-ethyl ether. Gravitational separation of the extract was used to record the first crystal structure of lucidin primeveroside, which is also the first ever known crystal structure of a glycoside containing anthraquinone moiety. The crystal structure along with (1)H and (13)C NMR helped elucidate and confirm the structure of this overlooked natural dye which has been shown to be a major compound in R. tinctorum L.

Background Most cases of human African trypanosomiasis (HAT) start with a bite from one of the subspecies of Glossina fuscipes. Tsetse use a range of olfactory and visual stimuli to locate their hosts and this response can be exploited to lure tsetse to insecticide-treated targets thereby reducing transmission. To provide a rational basis for cost-effective designs of target, we undertook studies to identify the optimal target colour. Methodology/Principal Findings On the Chamaunga islands of Lake Victoria , Kenya, studies were made of the numbers of G. fuscipes fuscipes attracted to targets consisting of a panel (25 cm square) of various coloured fabrics flanked by a panel (also 25 cm square) of fine black netting. Both panels were covered with an electrocuting grid to catch tsetse as they contacted the target. The reflectances of the 37 different-coloured cloth panels utilised in the study were measured spectrophotometrically. Catch was positively correlated with percentage reflectance at the blue (460 nm) wavelength and negatively correlated with reflectance at UV (360 nm) and green (520 nm) wavelengths. The best target was subjectively blue, with percentage reflectances of 3%, 29%, and 20% at 360 nm, 460 nm and 520 nm respectively. The worst target was also, subjectively, blue, but with high reflectances at UV (35% reflectance at 360 nm) wavelengths as well as blue (36% reflectance at 460 nm); the best low UV-reflecting blue caught 3× more tsetse than the high UV-reflecting blue. Conclusions/Significance Insecticide-treated targets to control G. f. fuscipes should be blue with low reflectance in both the UV and green bands of the spectrum. Targets that are subjectively blue will perform poorly if they also reflect UV strongly. The selection of fabrics for targets should be guided by spectral analysis of the cloth across both the spectrum visible to humans and the UV region., Author Summary Efforts to control human African trypanosomiasis (HAT) would be strengthened by the development and application of more cost-effective methods of controlling the various species of tsetse fly vector. Among the most promising approaches is the use of insecticide-treated targets which use various olfactory and visual stimuli to attract and kill tsetse. Following on from previous studies of the responses of tsetse to odours and target size and shape, we compared the numbers of G. f. fuscipes attracted to different coloured targets. Our results show that the attraction of tsetse is correlated positively with reflectance in the blue region of the spectrum but negatively with the UV- and green regions. The best blue targets attract and kill three times more tsetse than the worst because of different UV reflectance levels in the different blue cloths. Hence selecting fabrics for use in targets must be based on spectral analysis of the fabrics' reflectance across the spectrum visible to tsetse, which includes UV, and not simply on the ‘rule of thumb’ that targets to control tsetse should be blue.

Zinc Finger Nucleases (ZFNs) made by Context-Dependent Assembly (CoDA) and Transcription Activator-Like Effector Nucleases (TALENs) provide robust and user-friendly technologies for efficiently inactivating genes in zebrafish. These designer nucleases bind to and cleave DNA at particular target sites, inducing error-prone repair that can result in insertion or deletion mutations. Here, we assess the relative efficiencies of these technologies for inducing somatic DNA mutations in mosaic zebrafish. We find that TALENs exhibited a higher success rate for obtaining active nucleases capable of inducing mutations than compared with CoDA ZFNs. For example, all six TALENs tested induced DNA mutations at genomic target sites while only a subset of CoDA ZFNs exhibited detectable rates of mutagenesis. TALENs also exhibited higher mutation rates than CoDA ZFNs that had not been pre-screened using a bacterial two-hybrid assay, with DNA mutation rates ranging from 20%–76.8% compared to 1.1%–3.3%. Furthermore, the broader targeting range of TALENs enabled us to induce mutations at the methionine translation start site, sequences that were not targetable using the CoDA ZFN platform. TALENs exhibited similar toxicity to CoDA ZFNs, with >50% of injected animals surviving to 3 days of life. Taken together, our results suggest that TALEN technology provides a robust alternative to CoDA ZFNs for inducing targeted gene-inactivation in zebrafish, making it a preferred technology for creating targeted knockout mutants in zebrafish.

Background Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that is caused by the expansion of a polyglutamine (polyQ) stretch within Huntingtin (htt), the protein product of the HD gene. Although studies in vitro have suggested that the mutant htt can act in a potentially dominant negative fashion by sequestering wild-type htt into insoluble protein aggregates, the role of the length of the normal htt polyQ stretch, and the adjacent proline-rich region (PRR) in modulating HD mouse model pathogenesis is currently unknown. Results We describe the generation and characterization of a series of knock-in HD mouse models that express versions of the mouse HD gene (Hdh) encoding N-terminal hemaglutinin (HA) or 3xFlag epitope tagged full-length htt with different polyQ lengths (HA7Q-, 3xFlag7Q-, 3xFlag20Q-, and 3xFlag140Q-htt) and substitution of the adjacent mouse PRR with the human PRR (3xFlag20Q- and 3xFlag140Q-htt). Using co-immunoprecipitation and immunohistochemistry analyses, we detect no significant interaction between soluble full-length normal 7Q- htt and mutant (140Q) htt, but we do observe N-terminal fragments of epitope-tagged normal htt in mutant htt aggregates. When the sequences encoding normal mouse htt’s polyQ stretch and PRR are replaced with non-pathogenic human sequence in mice also expressing 140Q-htt, aggregation foci within the striatum, and the mean size of htt inclusions are increased, along with an increase in striatal lipofuscin and gliosis. Conclusion In mice, soluble full-length normal and mutant htt are predominantly monomeric. In heterozygous knock-in HD mouse models, substituting the normal mouse polyQ and PRR with normal human sequence can exacerbate some neuropathological phenotypes.

Cotton fiber cellulose is highly crystalline and oriented; when native cellulose (cellulose I) is treated with certain alkali concentrations, intermolecular hydrogen bonds are broken and Na-cellulose I is formed. At higher alkali concentrations Na-cellulose II forms, wherein intermolecular and intramolecular hydrogen bonds are broken, ultimately resulting in cellulose II polymers. Crystallinity changes in cotton fibers were observed and assigned using attenuated total reflectance Fourier transform infrared (ATR FT-IR) spectroscopy and X-ray diffraction (XRD) subsequent to sodium hydroxide treatment and compared with an in situ protein-binding methodology using cellulose-directed carbohydrate-binding modules (CBMs). Crystallinity changes observed using CBM probes for crystalline cellulose (CBM2a, CBM3a) and amorphous cellulose (CBM4-1, CBM17) displayed close agreement with changes in crystallinity observed with ATR-FTIR techniques, but it is notable that crystallinity changes observed with CBMs are observed at lower NaOH concentrations (2.0 mol dm(-3)), indicating these probes may be more sensitive in detecting crystallinity changes than those calculated using FTIR indices. It was observed that the concentration of NaOH at which crystallinity changes occur as analyzed using the CBM labeling techniques are also lower than those observed using X-ray diffraction techniques. Analysis of crystallinity changes in cellulose using CBMs offers a new and advantageous method of qualitative and quantitative assessment of changes to the structure of cellulose that occur with sodium hydroxide treatment.

The authors report a case of a 7-year-old girl with a progressive sensorimotor peripheral neuropathy with acute relapses associated with a desquamating purpuric rash, alopecia, and spinal cord atrophy. Distinctive features include systemic involvement with alopecia and rash, peripheral nervous system involvement with relapsing and remitting sensorimotor neuropathy, and central nervous system involvement with episodes of dystonic posturing and spinal cord atrophy. Extensive diagnostic evaluation for known causes of skin manifestations associated with peripheral neuropathy has failed to identify a cause for this patient’s condition. The authors discuss the case as an approach to the differential diagnosis and to highlight unusual features of this yet to be identified clinical entity.

SummaryEmbryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that ERMS-propagating potential is confined to myf5+ cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ ERMS cells reside adjacent normal muscle fibers. By late-stage ERMS, myf5+ cells are reorganized into distinct regions separated from differentiated tumor cells. Time-lapse imaging of late-stage ERMS revealed that myf5+ cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. Moreover, myogenin+ ERMS cells can enter the vasculature, whereas myf5+ ERMS-propagating cells do not. Our data suggest that non-tumor-propagating cells likely have important supportive roles in cancer progression and facilitate metastasis.

Self-renewing cancer cells are the only cell types within a tumor that have an unlimited ability to promote tumor growth, and are thus known as tumor-propagating cells, or tumor-initiating cells. It is thought that targeting these self-renewing cells for destruction will block tumor progression and stop relapse, greatly improving patient prognosis1. The most common way to determine the frequency of self-renewing cells within a tumor is a limiting dilution cell transplantation assay, in which tumor cells are transplanted into recipient animals at increasing doses; the proportion of animals that develop tumors is used the calculate the number of self-renewing cells within the original tumor sample2, 3. Ideally, a large number of animals would be used in each limiting dilution experiment to accurately determine the frequency of tumor-propagating cells. However, large scale experiments involving mice are costly, and most limiting dilution assays use only 10-15 mice per experiment. Zebrafish have gained prominence as a cancer model, in large part due to their ease of genetic manipulation and the economy by which large scale experiments can be performed. Additionally, the cancer types modeled in zebrafish have been found to closely mimic their counterpart human disease4. While it is possible to transplant tumor cells from one fish to another by sub-lethal irradiation of recipient animals, the regeneration of the immune system after 21 days often causes tumor regression5. The recent creation of syngeneic zebrafish has greatly facilitated tumor transplantation studies 6-8. Because these animals are genetically identical, transplanted tumor cells engraft robustly into recipient fish, and tumor growth can be monitored over long periods of time. Syngeneic zebrafish are ideal for limiting dilution transplantation assays in that tumor cells do not have to adapt to growth in a foreign microenvironment, which may underestimate self-renewing cell frequency9, 10. Additionally, one-cell transplants have been successfully completed using syngeneic zebrafish8 and several hundred animals can be easily and economically transplanted at one time, both of which serve to provide a more accurate estimate of self-renewing cell frequency. Here, a method is presented for creating primary, fluorescently-labeled T-cell acute lymphoblastic leukemia (T-ALL) in syngeneic zebrafish, and transplanting these tumors at limiting dilution into adult fish to determine self-renewing cell frequency. While leukemia is provided as an example, this protocol is suitable to determine the frequency of tumor-propagating cells using any cancer model in the zebrafish.

Executive Overview Moving from business as usual to a Total Quality Management (TQM) culture demands much from an organization. Nowhere in the organization is the demand more apparent or more important than in the human resource management function. Interviews with human resource professionals employed by winners of the Malcolm Baldrige National Quality Award provide insights into how HRM “best practices” support TQM cultures in these firms. Baldrige Award-winning companies have developed “portfolios” of human resource management policies to complement strategic TQM objectives. Aligning human resource practices with quality initiatives requires revolutionary changes in the way organizations train, empower, evaluate, and reward individuals and teams. However, the revolution is far from over. Even among organizations recognized for their TQM achievements, there is still a need for continuous improvement with respect to HR practices governing the selection, promotion, and development of future leaders. A pro...

This empirical study examines both the individual and combined effects of role uncertainty and role threat on managerial information search activity. Results from a survey of 215 managers in six organizations suggest that search is a function of a complex interaction between levels of uncertainty and threat in the role context. Findings suggest that previous conceptualizations of the relationships among uncertainty, threat, and search activity may have been overly simplistic.

To organize for innovation involves top management in a series of coordinated decisions about a number of different organizational characteristics. The decisions will be influenced greatly by the nature of the competitive environment and the type of innovation demanded by that environment. The interpretation of that environment will be greatly influenced by the nature of the firm's corporate culture as will the firm's goals, strategies, structures, technologies, systems, and people. An open and trusting culture tends to be supportive of innovation. There are a variety of structural options available depending on how management wishes to resolve a variety of different innovation tensions. Keywords: innovation; organization culture; organization design; organizational structure; innovation culture

Background Laboratory animal allergy (LAA) remains prevalent among workers exposed to laboratory animals. Pre-placement and health surveillance procedures vary between different employers. Aims To determine evidence-based strategies for pre-placement and periodic health assessments for workers exposed to laboratory animals. Methods Literature was searched systematically using Medline and EMBASE for articles published in all languages up to the end of May 2010. Evidence-based statements and recommendations were graded according to a modified Royal College of General Practitioner's star system. Results Hundred and nine studies were identified from the literature search; 59 of these were accessed for critical appraisal and 50 contributed to the evidence statements. Conclusions We recommend that laboratory animal workers should have a baseline health assessment that includes a health questionnaire, face-to-face assessment and spirometry. Identification of specific immunoglobulin E to common aero-allergens and to domestic and laboratory animal allergens may be used to identify workers who would benefit from further advice about managing their exposure, where risk assessment indicates that this might be prudent. Thereafter health surveillance should be performed by administering an appropriate health questionnaire, covering upper and lower respiratory, eye and skin symptoms on exposure, and wheals with animal scratches. The questionnaire should be administered at increased frequency for the first few years, the frequency being determined by a risk assessment. Where a worker develops new symptoms suggestive of LAA or where an asthmatic employee experiences deterioration either in symptoms or in control, they should be assessed further and a multicause multidisciplinary investigation performed.

Sex ratio adjustment (SRA) of broods has received widespread interest as a means for optimizing parental investment in offspring. Classical explanations for the evolution of SRA focus on improving offspring fitness in light of resource availability or mate attractiveness. Here, we use genetic models to demonstrate that SRA can evolve to alleviate sexual antagonism by improving the chance that the alleles of a sexually antagonistic trait are transmitted to the sex they benefit. In cases where the trait is autosomally inherited, this result is obtained regardless of whether SRA is based on the mother's or the father's genotype and irrespective of the recombination rate between the trait and SRA loci. SRA also evolves in this manner when the trait is sex-linked, provided that SRA decisions are based on the homogametic genotype (XX mothers or ZZ fathers). By contrast, when based on traits in the heterogametic sex, SRA promotes fixation of the allele that is detrimental to that sex, preventing the evolution of substantial levels of SRA. Our models indicate that the evolution of SRA in nature should be strongly influenced by the genetic architecture of the traits on which it is based and the form of selection affecting them.

Genetic mosaic analysis is a powerful technique to analyze the function of cells with varied genotypes in the same animal. By contrast, cell-lineage tracing allows the history of a cell's development to be uncovered. Zebrafish are uniquely suited to merge mosaic and cell lineage studies, and in this issue of Nature Methods, Russell Collins and colleagues present the first non-invasive method of generating temporally and spatially controlled mosaics in zebrafish1.

This appendix section of this book titled The Sun Rises A Shamans Chant, Ritual Exchange and Fertility in the Apatani Valley presents the outline of Murung events. The outline lists only important events during an elaborate Murung. Most Murungs begin in the first week of January and preparations get underway in November or before. It lists the day to day events of the Murung festival like rice donations on the second day, pig sacrifice on the seventh day of the festival and a picnic in the forest is the last event of the festival.Keywords: Apatani valley; Murung events

This section presents the transcription of the Subu Heniin text recited by Mudan Pai in his house during four days in 2004 and translated in chapter 6. He chanted these words in a steady, measured pace, broken only by a pause between phrases, which are separated by commas in the transcription. An extended pause after two or three phrases marks the end of one 'line' and the beginning of another. Occasionally, Mudan Pai chanted only one phrase before pausing and moving to a new line. Mudan Pai, like most nyibus, chanted a line of two or three phrases approximately every ten seconds and about five or six lines every minute. Such uninterrupted chanting did not continue for long, however, and the normal breaks, plus unexpected problems, meant that he chanted 250-300 lines an hour.Keywords: Mudan Pai; Subu Heniin

This chapter describes features of Subu Heniin text, while considering alongside, other lengthy ritual recitations. The primary purpose of Subu Heniin chant is to foster prosperity, by contacting protective spirits, on behalf of the husband and wife who sponsor the festival. The exfoliation of life from the female body is more than a repeated image in the Subu Heniin text. The Subu Heniin begins with the rising sun, whose light and heat lead to birth and fertility. It is equally revealing that water, the other half of life, is born at a convergence where clansmen cooperate. Fertility is expressed in these images of the rising sun, dividing female body, converging streams and expanding bamboo. The bamboo is important also because it introduces the ritual journey, the second theme of the Subu Heniin text.Keywords: expanding bamboo; female body; ritual chants; Subu Heniin text

At the Murung festival, the principal purpose for Apatanis is to make contact with the spirits. Everything depends on clear communication with them, and that requires the niyubu because only he can speak to the spirits in their language. an Apatani niyubu does not retrieve fugitive souls and spirit possession does occur but not to a nyibu. Although the niyubu chant contains a great deal of information (about spirits, ancestors, cosmology), the performance does not convey content. Instead, it communicates a sense of coherence. Standing on the lapang, unmistakable in his costume and speaking like no one else, the niyubu is a singular representation of tradition. A niyubus performance is overheard rather than heard. A discursive universe, hovering somewhere between imagination and experience, would describe the niyubu and his ritual speech, as well.Keywords: Apatanis; communication withspirits; Murung festival; niyubu performer