Complexity in influenza virus targeted drug design: interaction with human sialidases.

With the global spread of the pandemic H1N1 and the ongoing pandemic potential of the H5N1 subtype, the influenza virus represents one of the most alarming viruses spreading worldwide. The influenza virus sialidase is an effective drug target, and a number of inhibitors are clinically effective against the virus (zanamivir, oseltamivir, peramivir). Here we report structural and biochemical studies of the human cytosolic sialidase Neu2 with influenza virus sialidase-targeting drugs and related compounds

Economic losses from US hurricanes consistent with an influence from climate change

Warming of the climate system and its impacts on biophysical and human systems have been widely documented. The frequency and intensity of extreme weather events have also changed, but the observed increases in natural disaster losses are often thought to result solely from societal change, such as increases in exposure and vulnerability. Here we analyse the economic losses from tropical cyclones in the United States, using a regression-based approach instead of a standard normalization procedure to changes in exposure and vulnerability, to minimize the chance of introducing a spurious trend. Unlike previous studies, we use statistical models to estimate the contributions of socioeconomic factors to the observed trend in losses and we account for non-normal and nonlinear characteristics of loss data. We identify an upward trend in economic losses between 1900 and 2005 that cannot be explained by commonly used socioeconomic variables. Based on records of geophysical data, we identify an upward trend in both the number and intensity of hurricanes in the North Atlantic basin as well as in the number of loss-generating tropical cyclone records in the United States that is consistent with the smoothed global average rise in surface air temperature. We estimate that, in 2005, US$2 to US$14 billion of the recorded annual losses could be attributable to climate change, 2 to 12% of that year’s normalized losses. We suggest that damages from tropical cyclones cannot be dismissed when evaluating the current and future costs of climate change and the expected benefits of mitigation and adaptation strategies

The hit-and-return system enables efficient time-resolved serial synchrotron crystallography

We present a ‘hit-and-return’ (HARE) method for time-resolved serial synchrotron crystallography with time resolution from milliseconds to seconds or longer. Timing delays are set mechanically, using the regular pattern in fixed-target crystallography chips and a translation stage system. Optical pump-probe experiments to capture intermediate structures of fluoroacetate dehalogenase binding to its ligand demonstrated that data can be collected at short (30 ms), medium (752 ms) and long (2,052 ms) intervals

Synaptotagmin-like proteins control the formation of a single apical membrane domain in epithelial cells

The formation of epithelial tissues requires both the generation of apical-basal polarity and the coordination of this polarity between neighbouring cells to form a central lumen. During de novo lumen formation, vectorial membrane transport contributes to the formation of a singular apical membrane, resulting in the contribution of each cell to only a single lumen. Here, from a functional screen for genes required for three-dimensional epithelial architecture, we identify key roles for synaptotagmin-like proteins 2-a and 4-a (Slp2-a/4-a) in the generation of a single apical surface per cell. Slp2-a localizes to the luminal membrane in a PtdIns(4,5)P(2)-dependent manner, where it targets Rab27-loaded vesicles to initiate a single lumen. Vesicle tethering and fusion is controlled by Slp4-a, in conjunction with Rab27/Rab3/Rab8 and the SNARE syntaxin-3. Together, Slp2-a/4-a coordinate the spatiotemporal organization of vectorial apical transport to ensure that only a single apical surface, and thus the formation of a single lumen, occurs per cell