p190RhoGAP is cell cycle regulated and affects cytokinesis

p190RhoGAP (p190), a Rho family GTPase-activating protein, regulates actin stress fiber dynamics via hydrolysis of Rho-GTP. Recent data suggest that p190 also regulates cell proliferation. To gain insights into the cellular process(es) affected by p190, we altered its levels by conditional or transient overexpression. Overexpression of p190 resulted in a multinucleated phenotype that was dependent on the GTPase-activating protein domain. Confocal immunofluorescence microscopy revealed that both endogenous and exogenous p190 localized to the newly forming and contracting cleavage furrow of dividing cells. However, overexpression of p190 resulted in abnormal positioning of the furrow specification site and unequal daughter cell partitioning, as well as faulty furrow contraction and multinucleation. Furthermore, levels of endogenous p190 protein were transiently decreased in late mitosis via an ubiquitin-mediated degradation process that required the NH2-terminal GTP-binding region of p190. These results suggest that a cell cycle–regulated reduction in endogenous p190 levels is linked to completion of cytokinesis and generation of viable cell progeny

Incorporating Financial Statement Information to Improve Forecasts of Corporate Taxable Income

We contribute to the research on the information content of earnings as it applies to the forecasting of economic activity across reporting models. We examine whether publicly available financial statement information is incrementally useful in forecasting confidentially reported taxable income. More precise firm-level taxable income forecasts can improve policymakers’ modeling of the tax system and their ability to analyze the effect of proposed changes in corporate tax law. When aggregated, improved micro-forecasts can also yield more accurate macro-forecasts of corporate taxable income, a significant component of the federal budget. We find that financial statement information improves firm-level estimates of future taxable income by providing more timely information. We also document the usefulness of the deferred tax valuation allowance in improving taxable income estimates for loss firms. Our evidence suggests public financial statement information complements proprietary data to improve estimates of future taxable income for budgetary and policy use

Body mass index, prudent diet score and social class across three generations: evidence from the Hertfordshire Intergenerational Study.

BACKGROUND: Studies describing body mass index (BMI) and prudent diet score have reported that they are associated between parents and children. The Hertfordshire Intergenerational Study, which contains BMI, diet and social class information across three generations, provides an opportunity to consider the influence of grandparental and parental BMI and prudent diet score across multiple generations, and the influence of grandparental and parental social class on child BMI. METHODS: Linear regressions examining the tracking of adult BMI and prudent diet score across three generations (grandparent (F0), parent (F1) and child (F2)) were run from parent to child and from grandparent to grandchild. Linear mixed models investigated the influence of F0 and F1 BMI or prudent diet score on F2 BMI and prudent diet score. Linear regressions were run to determine whether social class and prudent diet score of parents and grandparents influenced the BMI of children and grandchildren. RESULTS: BMI was significantly associated across each generational pair and from F0 to F1 in multilevel models. Prudent diet score was significantly positively associated between grandparents and grandchildren. Lower grandparental and parental social class had a significantly positive association with F2 BMI (F0 low social class: b=1.188 kg/m2, 95% CI 0.060 to 2.315, p=0.039; F1 middle social class: b=2.477 kg/m2, 95% CI 0.726 to 4.227, p=0.006). CONCLUSION: Adult BMI tracks across generations of the Hertfordshire Intergenerational Study, and child BMI is associated with parental and grandparental social class. The results presented here add to literature supporting behavioural and social factors in the transmission of BMI across generations

PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition

Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of PTEN mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to inhibition of dihydroorotate dehydrogenase, a rate limiting enzyme for pyrimidine ring synthesis. S-phase PTEN mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in PTEN deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN mutant cancers

Marine Noise Pollution - Increasing Recognition But Need for More Practical Action

Over the last two decades, marine noise pollution has become increasingly recognized as an issue of major significance. The issue has become a primary focus of marine mammal research, but is also of concern to the public and policy makers. The result has been efforts involving a variety of disciplines, and relevant legislation and associated guidance are now in place in many parts of the world. Most current mitigation efforts are directed at reducing the risk of injury from exposure to intense noise, although the effectiveness of such mitigation measures in terms of risk reduction has rarely been quantified. Longer-term chronic impacts of noise including disturbance or masking of sounds critical for feeding and reproduction have received substantially less attention in management. New technologies are being developed for a number of activities which can substantially reduce noise inputs into the marine environment. As with other forms of pollution, reducing input at source is likely to be the most effective way of reducing impacts. We recommend as a priority the implementation of noise quieting technologies and the spatial and temporal exclusion of noise to minimize contact with marine life

Tumour Lysis Syndrome Occurring in a Patient with Metastatic Gastrointestinal Stromal Tumour Treated with Glivec (Imatinib Mesylate, Gleevec, STI571)

Tumour lysis syndrome (TLS) is a rare side effect of chemotherapy for solid tumours. It describes the metabolic derangements following rapid and extensive tumour cell death following a good response to chemotherapy. Symptoms are those of metabolic derangement and renal failure. Treatment involves rehydration and correction of metabolic abnormalities. TLS should be considered in high risk groups. We report a case of TLS in a patient with metastatic gastrointestinal stromal tumour treated with imatinib mesylate. To our knowledge, this is the first reported case

Inclusive research in education: contributions to method and debate

Education is not necessarily associated with inclusive research and the label of inclusive research is little used in our discipline. It is an umbrella term encompassing participatory, emancipatory and community/peer-led research. This is research in which those (such as learners and teachers) who tend to be the objects of other people’s research become agents in the conduct of research, ensuring that such research addresses issues that are important to them and includes their views and experiences (see Walmsley & Johnson, 2003 and Nind, 2014 for more on definitions). Conceptualising some research as inclusive is part of a concern with the democratization of the research process and with social justice - in and through - research; it represents an interest in the people outside of academia being active and credible producers of knowledge

Mitigating alemtuzumab-associated autoimmunity in MS: A whack-a-mole B-cell depletion strategy

Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity. Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy. Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed. Conclusions: An anti-CD20 whack-a-mole B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation. Classification of evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases

Reflections on the role of the ‘users’: challenges in a multi-disciplinary context of learner-centred design for children on the autism spectrum

Technology design in the field of human–computer interaction has developed a continuum of participatory research methods, closely mirroring methodological approaches and epistemological discussions in other fields. This paper positions such approaches as examples of inclusive research (to varying degrees) within education, and illustrates the complexity of navigating and involving different user groups in the context of multi-disciplinary research projects. We illustrate this complexity with examples from our recent work, involving children on the autism spectrum and their teachers. Both groups were involved in learner-centred design processes to develop technologies to support social conversation and collaboration. We conceptualize this complexity as a triple-decker ‘sandwich’ representing Theory, Technologies and Thoughts and argue that all three layers need to be appropriately aligned for a good quality ‘product’ or outcome. However, the challenge lies in navigating and negotiating all three layers at the same time, including the views and experiences of the learners. We question the extent to which it may be possible to combine co-operative, empowering approaches to participatory design with an outcome-focused agenda that seeks to develop a robust learning technology for use in real classrooms

Src-dependent Phosphorylation of the Epidermal Growth Factor Receptor on Tyrosine 845 Is Required for Zinc-induced Ras Activation

Previous studies have shown that exposure of cells to Zn2+ ions induces Ras and MAPK activation through the EGF receptor (EGFR). To further determine the role of EGFR in Zn2+-induced signaling, mouse B82L fibroblasts expressing no detectable EGFR protein (B82L-par), wild type EGFR (B82L-wt), kinase-deficient EGFR (B82L-K721M), or COOH-truncated EGFR (B82L-c'958) were tested. Exposure to Zn2+ induced Ras activity in B82L-wt, B82L-K721M, and B82L-c'958 but not in B82L-par cells, indicating that the tyrosine kinase domain and the auto-phosphorylation sites of the EGFR were not required for Zn2+-induced Ras activation. Zn2+ induced Src activation in all B82L cell lines, including B82L-par, indicating that Src activation is independent of the presence of the EGFR. A Src kinase inhibitor blocked Zn2+-induced Ras activation in all the B82L cell lines capable of this response, suggesting the involvement of Src kinase in Zn2+-induced Ras activation via the EGFR. Zn2+ induced the association of the EGFR with Src and specifically increased the phosphorylation of EGFR at tyrosine 845 (Tyr-845), a known Src phosphorylation site. Stably transfected B82L cells with a point mutation of the EGFR at Tyr-845 (B82L-Y845F) exhibited only basal Ras activity following exposure to Zn2+. These data demonstrate that Src-dependent phosphorylation of the EGFR at Tyr-845 is required for EGFR transactivation and Zn2+-induced Ras activation