Mechanistic mathematical modelling of mercaptopurine effects on cell cycle of human acute lymphoblastic leukaemia cells

The antimetabolite mercaptopurine (MP) is widely used to treat childhood acute lymphoblastic leukaemia (ALL). To study the dynamics of MP on the cell cycle, we incubated human T-cell leukaemia cell lines (Molt-4 sensitive and resistant subline and P12 resistant) with 10 μM MP and measured total cell count, cell cycle distribution, percent viable, percent apoptotic, and percent dead cells serially over 72 h. We developed a mathematical model of the cell cycle dynamics after treatment with MP and used it to show that the Molt-4 sensitive controls had a significantly higher rate of cells entering apoptosis (2.7-fold, P<0.00001) relative to the resistant cell lines. Additionally, when treated with MP, the sensitive cell line showed a significant increase in the rate at which cells enter apoptosis compared to its controls (2.4-fold, P<0.00001). Of note, the resistant cell lines had a higher rate of antimetabolite incorporation into the DNA of viable cells (>1.4-fold, P<0.01). Lastly, in contrast to the other cell lines, the Molt-4 resistant subline continued to cycle, though at a rate slower relative to its control, rather than proceed to apoptosis. This led to a larger S-phase block in the Molt-4 resistant cell line, but not a higher rate of cell death. Gene expression of apoptosis, cell cycle, and repair genes were consistent with mechanistic dynamics described by the model. In summary, the mathematical model provides a quantitative assessment to compare the cell cycle effects of MP in cells with varying degrees of MP resistance

Structure vulnerability and risk analysis of 4-legged offshore structure

Offshore structures are commonly used in oil and gas collecting sector. This industry is one of the major economic sector in Malaysia. Since distant earthquakes from neighbour countries (Indonesia and Philippines) had caused significant structural damages in the past few years, the perfomance level of offshore due to seismic effect need to be undergone detailed investigation. Therefore, this research aims to investigate the vulnerability and analyze the risk of 4-legged fixed offshore structure under different excitations. In order to achieve the objectives, SAP 2000 was chosen to analyze the offshore structure modelling by referring to the API (American Petroleum Institute) criteria. Time history, response spectrum and free vibration analysis have been performed. The behaviour of the offshore structure was observed and evaluated through the natural frequencies and periods. Meanwhile, results outcome of the joint displacement, velocity, and acceleration represented the dynamic characteristic of the structure. The 4-legged fixed offshore structure categorized as Immediate Occupancy (IO) based on FEMA 356 guidelines. From the results, it showed that existing 4-legged offshore structures in Malaysia are capable to resist seismic loads and in stable condition

Squalus acanthias, spiny dogfish

While there are reported subpopulations of Squalus acanthias (Linnaeus, 1758) elsewhere in the world, the North Pacific subpopulation is now considered a separate species, Squalus suckleyi (Girard, 1854) (see Ebert et al. 2010). Further taxonomic studies on this genus are required, including in relation to Mediterranean and Black Sea subpopulations. In Europe, three subpopulations are inferred to occur.Fil: Finucci, B.. National Institute of Water and Atmospheric Research; Nueva ZelandaFil: Cheok, J.. University Fraser Simon; CanadáFil: Chiaramonte, Gustavo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Hidrobiológica de Puerto Quequén (sede Quequén); ArgentinaFil: Cotton, C. F.. Florida State University; Estados UnidosFil: Dulvy, N. K.. University Fraser Simon; CanadáFil: Kulka, D. W.. No especifíca; ArgentinaFil: Neat, F. C.. No especifíca; ArgentinaFil: Pacoureau, N.. University Fraser Simon; CanadáFil: Rigby, C. L.. James Cook University; AustraliaFil: Tanaka, S.. No especifíca; ArgentinaFil: Walker, T. I.. University of Melbourne; Australi

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Towards a New Paradigm for Intuitive Theatrical Lighting Control

A simplified model of a lighting process applied in theatrical productions is one that involves two key players. The first is that of the lighting designer, to produce a set of intentions and plans for the scenes that define the show. The second, the lighting technician, has the job of translating these designs into practice using control equipment, luminaires, and other technical instruments. The lighting design often becomes a ‘working document’ subject to change and adaptation as the physical reality of the design becomes apparent, and the input of other stakeholders is considered. This process can be a valuable creative tool, and also a difficult technical hurdle to overcome, depending on a varied number of factors. A common frustration with this process is that either the complexity of the task, or difficulty in communication can make it difficult for the final creative vision to be effectively realised. Strains may also arise in the case of small, often touring, theatre companies where the lighting designer and technician may be the same person, and frequently one of the performers as well. Considering the design aspect, there can be challenges in ensuring efficacy of lighting plans between venues in touring productions, with 2D lighting sketches or even 3D computer simulations confined to the paper or screen. From a technical perspective, the role of the lighting technician in theatres and performance situations has included the operation of lighting control equipment during shows. The equipment has evolved over time but has, until recently, been grounded upon the basis of faders and the mixing desk. It is argued that this paradigm has failed to keep pace with the change in other interactive technologies. The on-going research described in this paper explores existing and upcoming technologies in the field, whilst also seeking to understand the roles and communication workflows of those involved in theatrical lighting to find the best areas to seek improvement, adopting principles of user-centred design. The intention of this research is to develop a new paradigm, and manifestation of it, using a control method for lighting or projection that allows a more intuitive form of operation in theatre productions, which will be scalable and flexible

Overfishing Drives Over One-Third of All Sharks and Rays Toward a Global Extinction Crisis

The scale and drivers of marine biodiversity loss are being revealed by the International Union for Conservation of Nature (IUCN) Red List assessment process. We present the first global reassessment of 1,199 species in Class Chondrichthyes-sharks, rays, and chimeras. The first global assessment (in 2014) concluded that one-quarter (24%) of species were threatened. Now, 391 (32.6%) species are threatened with extinction. When this percentage of threat is applied to Data Deficient species, more than one-third (37.5%) of chondrichthyans are estimated to be threatened, with much of this change resulting from new information. Three species are Critically Endangered (Possibly Extinct), representing possibly the first global marine fish extinctions due to overfishing. Consequently, the chondrichthyan extinction rate is potentially 25 extinctions per million species years, comparable to that of terrestrial vertebrates. Overfishing is the universal threat affecting all 391 threatened species and is the sole threat for 67.3% of species and interacts with three other threats for the remaining third: loss and degradation of habitat (31.2% of threatened species), climate change (10.2%), and pollution (6.9%). Species are disproportionately threatened in tropical and subtropical coastal waters. Science-based limits on fishing, effective marine protected areas, and approaches that reduce or eliminate fishing mortality are urgently needed to minimize mortality of threatened species and ensure sustainable catch and trade of others. Immediate action is essential to prevent further extinctions and protect the potential for food security and ecosystem functions provided by this iconic lineage of predators

Gebiss: an ImageJ plugin for the specification of ground truth and the performance evaluation of 3D segmentation algorithms.

Background: Image segmentation is a crucial step in quantitative microscopy that helps to define regions of tissues, cells or subcellular compartments. Depending on the degree of user interactions, segmentation methods can be divided into manual, automated or semi-automated approaches. 3D image stacks usually require automated methods due to their large number of optical sections. However, certain applications benefit from manual or semi-automated approaches. Scenarios include the quantification of 3D images with poor signal-to-noise ratios or the generation of so-called ground truth segmentations that are used to evaluate the accuracy of automated segmentation methods. Results: We have developed Gebiss; an ImageJ plugin for the interactive segmentation, visualisation and quantification of 3D microscopic image stacks. We integrated a variety of existing plugins for threshold-based segmentation and volume visualisation. Conclusions: We demonstrate the application of Gebiss to the segmentation of nuclei in live Drosophila embryos and the quantification of neurodegeneration in Drosophila larval brains. Gebiss was developed as a cross-platform ImageJ plugin and is freely available on the web at http://imaging.bii.a-star.edu.sg/projects/gebiss

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)