One potential physiological target for new antischistosomals is the parasite's system for excretion of wastes and xenobiotics. P-glycoprotein (Pgp), a member of the ATP-binding cassette superfamily of proteins, is an ATP-dependent efflux pump involved in transport of toxins and xenobiotics from cells. In vertebrates, increased expression of Pgp is associated with multidrug resistance in tumor cells. Pgp may also play a role in drug resistance in helminths. In this report, we examine the relationship between praziquantel (PZQ), the current drug of choice against schistosomiasis, and Pgp expression in Schistosoma mansoni. We show that levels of RNA for SMDR2, a Pgp homolog from S. mansoni, increase transiently in adult male worms following exposure to sublethal concentrations (100 -500 nM) of PZQ. A corresponding, though delayed, increase in anti-Pgp immunoreactive protein expression occurs in adult males following exposure to PZQ. The level of anti-Pgp immunoreactivity in particular regions of adult worms also increases in response to PZQ. Adult worms from an Egyptian S. mansoni isolate with reduced sensitivity to PZQ express increased levels of SMDR2 RNA and anti-Pgp-immunoreactive protein, perhaps indicating a role for multidrug resistance proteins in development or maintenance of PZQ resistance.

We are interested in the problem of tracking broad topics such as "baseball" and "fashion" in continuous streams of short texts, exemplified by tweets from the microblogging service Twitter. The task is conceived as a language modeling problem where per-topic models are trained using hashtags in the tweet stream, which serve as proxies for topic labels. Simple perplexity-based classifiers are then applied to filter the tweet stream for topics of interest. Within this framework, we evaluate, both intrinsically and extrinsically, smoothing techniques for integrating "foreground" models (to capture recency) and "background" models (to combat sparsity), as well as different techniques for retaining history. Experiments show that unigram language models smoothed using a normalized extension of stupid backoff and a simple queue for history retention performs well on the task.

Arginyltransferase 1 (Ate1) mediates protein arginylation, a poorly understood protein posttranslational modification (PTM) in eukaryotic cells. Previous evidence suggest a potential involvement of arginylation in stress response and this PTM was traditionally considered anti-apoptotic based on the studies of individual substrates. However, here we found that arginylation promotes cell death and/or growth arrest, depending on the nature and intensity of the stressing factor. Specifically, in yeast, mouse and human cells, deletion or downregulation of the ATE1 gene disrupts typical stress responses by bypassing growth arrest and suppressing cell death events in the presence of disease-related stressing factors, including oxidative, heat, and osmotic stresses, as well as the exposure to heavy metals or radiation. Conversely, in wild-type cells responding to stress, there is an increase of cellular Ate1 protein level and arginylation activity. Furthermore, the increase of Ate1 protein directly promotes cell death in a manner dependent on its arginylation activity. Finally, we found Ate1 to be required to suppress mutation frequency in yeast and mammalian cells during DNA-damaging conditions such as ultraviolet irradiation. Our study clarifies the role of Ate1/arginylation in stress response and provides a new mechanism to explain the link between Ate1 and a variety of diseases including cancer. This is also the first example that the modulation of the global level of a PTM is capable of affecting DNA mutagenesis.

The ATP-binding cassette (ABC) superfamily of proteins comprises several ATP-dependent efflux pumps involved in transport of toxins and xenobiotics from cells. These transporters are essential components of normal physiology, and a subset is associated with development of multidrug resistance. P-glycoprotein (Pgp) and the multidrug resistance-associated proteins (MRPs) represent two classes of these multidrug resistance (MDR) transporters. MRP1 is one type of mammalian MRP, which preferentially transports anionic compounds and compounds detoxified by cellular enzymes such as glutathione-S-transferase. It also transports signaling molecules, including immunomodulators. In schistosomes, both Pgp and MRP substrates localize to the excretory system, a potentially attractive target for new antischistosomals. We have previously shown that expression of schistosome Pgp (SMDR2) is altered in worms exposed to praziquantel (PZQ), the current drug of choice against schistosomiasis, and is expressed at higher levels in worms from isolates with reduced PZQ susceptibility. We have also shown that PZQ interacts directly with SMDR2. Here, we examine the relationship between PZQ and SmMRP1, a Schistosoma mansoni homolog of mammalian MRP1. SmMRP1 RNA is differentially expressed in adult males and females, and levels increase transiently following exposure of adult worms to sub-lethal concentrations of PZQ. A corresponding, though delayed, increase in anti-MRP1 immunoreactive protein also occurs following exposure to PZQ. PZQ-insensitive juvenile worms express higher levels of both SmMRP1 and SMDR2 RNA than mature adults, consistent with the hypothesis that increases in levels of schistosome multidrug transporters may be involved in development or maintenance of reduced susceptibility to PZQ.