Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.     

Formalising and Detecting Community Structures in Real World Complex Networks

Community structure is an integral characteristic of real world networks whichever processes or areas they emerge from. This paper addresses the problem of community structure detection theoretically as well as computationally. The authors introduce a number of concepts such as the neighbourhood and strength of a subgraph, p-community, local maximal p-community, hubs, and outliers that play elemental role in formalising the concept of community structure in complex networks. A few preliminary results have been derived that lead to the development of an algorithm for community structure detection in undirected unweighted networks. The algorithm is based on a local seed expansion strategy that uses the concept of interaction coefficient. The authors have analysed the algorithm on a number of parameters such as accuracy, stability, and quality on synthetic and real world networks from different areas.     

Serum desoxy-ribose compounds in experimental myocardial infarction

Zusammenfassung Es wird nachgewiesen, dass eine koronare Unterbindung am Hund zu erhöhter Desoxyriboseverbindung im Serum führt.

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This work was supported by a grant from Indian Council of Medical Research.     

A Cenozoic record of the equatorial Pacific carbonate compensation depth

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5?kilometres during the early Cenozoic (approximately 55?million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.     

Three dimensional Couette flow and heat transfer through a porous medium with variable permeability

This paper reports research on the effects of variations in injection velocity and permeability on the heat transfer and flow through a highly porous medium between two horizontal parallel plates situated at constant distance with constant suction by the upper plate.Due to this type of variation in injection velocity and in permeability the flow becomes three dimensional.The governing equstions are solved by adopting complex variable notations to obtain the expressions for the velocity and temperature field.The skin-friction along the main flow direction and rate of heat transfer are discussed with the help of graphs.     

Tetrazolium salt: Antagonism of acetylcholine-induced response on frog's rectus

Zusammenfassung Es wurde die Wirkung eines Tetrazolsalzes (2:3:5, Triphenyl-Tetrazolium-Chlorid) auf die durch Acetylcholin hervorgerufene Kontraktion des M. rectus abdominis beim Frosch geprüft. In verhältnismässig niedriger Dosierung verhält sich die Substanz wie ein kompetitiver Hemmer des Acetylcholins, während sich dieser Effekt in höherer Dosierung als nichtkompetitiv erwies.