Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium Tuberculosis Proteasome

The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans. Selective inhibitors of the Mtb 20S were designed and synthesized on the bases of both its unique substrate preferences and the structures of substrate-mimicking covalent inhibitors of eukaryotic proteasomes called syringolins. Unlike the parent syringolins, the designed analogues weakly inhibit the human 20S (Hs 20S) proteasome and preferentially inhibit Mtb 20S over the human counterpart by as much as 74-fold. Moreover, they can penetrate the mycobacterial cell envelope and render Mtb susceptible to nitric oxide-mediated stress. Importantly, they do not inhibit the growth of human cell lines in vitro and thus may be starting points for tuberculosis drug development.National Institutes of Health (U.S.) (Grant AI-16892

Музейна справа сучасної Франції на прикладі музею Бранлі

The article sums up the results of the first year of operation du quai Braniy. It also sheds light on multicultural image of modern France

Validation of Tikhonov adaptively regularized gamma variate fitting with 24-h plasma clearance in cirrhotic patients with ascites

PURPOSE: The aim was to compare late-time extrapolation of plasma clearance (CL) from Tikhonov adaptively regularized gamma variate fitting (Tk-GV) and from mono-exponential (E1) fitting. METHODS: Ten (51)Cr-ethylenediaminetetraacetic acid bolus IV studies in adults--8 with ascites--assessed for liver transplantation, with 12-16 plasma samples drawn from 5-min to 24-h, were fit with Tk-GV and E1 models and CL results were compared using Passing-Bablok fitting. RESULTS: The 24-h CL(Tk-GV) values ranged from 11.4 to 79.7 ml/min. Linear regression of 4- versus 24-h CL(Tk-GV) yielded no significant departure from a slope of 1, whereas the 4- versus 24-h CL(E1) slope, 1.56, was significantly increased. For CL(Tk-GV-24-h) versus CL(E1-24-h), there was a biased slope and intercept (0.85, 5.97 ml/min). Moreover, the quality of fitting of 24-h data was significantly better for Tk-GV than for E1, as follows. For 10 logarithm of concentration curves, higher r values were obtained for each Tk-GV fit (median 0.998) than for its corresponding E1 fit (median 0.965), with p < 0.0001 (paired t-test of z-statistics from Fisher r-z transformations). The E1 fit quality degraded with increasing V/W [volume of distribution (l) per kg body weight, p = 0.003]. However, Tk-GV fit quality versus V/W was uncorrelated (p = 0.8). CONCLUSION: CL(E1) values were dependent on sample time and the quality of fit was poor and degraded with increasing ascites, consistent with current opinion that CL(E1) is contraindicated in ascitic patients. CL(Tk-GV) was relatively more accurate and the good quality of fit was unaffected by ascites. CL(Tk-GV) was the preferred method for the accurate calculation of CL and was useful despite liver failure and ascites

The use of high aspect ratio photoresist (SU-8) for super-hydrophobic pattern prototyping

In this work we present a reliable technique for the production of large areas of high aspect-ratio patterns and describe their use as model super-hydrophobic systems. The high thickness and straight sidewalls possible with SU-8 were used to generate dense patterns of small pillars. These photoresist patterns could be used directly, without the need for micromoulding. A method is given allowing resist thickness to be varied over a wide range and a bottom antireflective layer was used to simplify patterning on reflective substrates. This patterning technique allows rapid testing of wetting theories, as pattern size and depth can be varied simply and samples can be produced in sufficient numbers for laboratory use. We show how the static contact angle of water varies with pattern height for one sample-pattern and how static and dynamic contact angles vary with dimension using high aspect-ratio patterns

Nodal dynamics, not degree distributions, determine the structural controllability of complex networks

Structural controllability has been proposed as an analytical framework for making predictions regarding the control of complex networks across myriad disciplines in the physical and life sciences (Liu et al., Nature:473(7346):167-173, 2011). Although the integration of control theory and network analysis is important, we argue that the application of the structural controllability framework to most if not all real-world networks leads to the conclusion that a single control input, applied to the power dominating set (PDS), is all that is needed for structural controllability. This result is consistent with the well-known fact that controllability and its dual observability are generic properties of systems. We argue that more important than issues of structural controllability are the questions of whether a system is almost uncontrollable, whether it is almost unobservable, and whether it possesses almost pole-zero cancellations.Comment: 1 Figures, 6 page

On the evolutionary origin of aging

It is generally believed that the first organisms did not age, and that aging thus evolved at some point in the history of life. When and why this transition occurred is a fundamental question in evolutionary biology. Recent reports of aging in bacteria suggest that aging predates the emergence of eukaryotes and originated in simple unicellular organisms. Here we use simple models to study why such organisms would evolve aging. These models show that the differentiation between an aging parent and a rejuvenated offspring readily evolves as a strategy to cope with damage that accumulates due to vital activities. We use measurements of the age-specific performance of individual bacteria to test the assumptions of the model, and find evidence that they are fulfilled. The mechanism that leads to aging is expected to operate in a wide range of organisms, suggesting that aging evolved early and repeatedly in the history of life. Aging might thus be a more fundamental aspect of cellular organisms than assumed so far

Sediment pumping by tidal asymmetry in a partially mixed estuary

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 112 (2007): C07028, doi:10.1029/2006JC003784.Observations collected at two laterally adjacent locations are used to examine the processes driving sediment transport in the partially mixed York River Estuary. Estimates of sediment flux are decomposed into advective and pumping components, to evaluate the importance of tidal asymmetries in turbulent mixing. At the instrumented location in the estuarine channel, a strong asymmetry in internal mixing due to tidal straining is documented, with higher values of eddy viscosity occurring during the less-stratified flood tide. As a result of this asymmetry, more sediment is resuspended during the flood phase of the tide resulting in up-estuary pumping of sediment despite a net down-estuary advective flux. At the instrumented location on the adjacent shoal, where no pronounced tidal asymmetry in internal mixing was found, both the pumping flux and advective flux were directed down-estuary. The down-estuary pumping of sediment on the shoal appears to be driven by asymmetries in bed stress. The impact of tidal asymmetries in bed stress at the channel location was negated because the amount of sediment available for resuspension was limited. As a result, the pumping flux was dominated by the overlying asymmetries in internal mixing. The asymmetries in stratification appear to exert an important control on the vertical distribution of sediment by both impacting the eddy diffusivity as well as the fall velocity. During the more turbulent flood tide, the fall velocities are smaller suggesting the Kolmogorov microscale is setting the upper bound on floc diameter.Support for this research at VIMS was provided by the National Science Foundation Division of Ocean Sciences grants OCE-9984941 and OCE-0536572

Abrupt reversal in emissions and atmospheric abundance of HCFC-133a (CF3CH2Cl)

Hydrochlorofluorocarbon HCFC-133a (CF3CH2Cl) is an anthropogenic compound whose consumption for emissive use is restricted under the Montreal Protocol. A recent study showed rapidly increasing atmospheric abundances and emissions. We report that, following this rise, the at- mospheric abundance and emissions have declined sharply in the past three years. We find a Northern Hemisphere HCFC-133a increase from 0.13 ppt (dry air mole fraction in parts-per-trillion) in 2000 to 0.50 ppt in 2012–mid-2013 followed by an abrupt reversal to 0.44 ppt by early 2015. Global emissions derived from these observations peaked at 3.1 kt in 2011, followed by a rapid decline of 0.5 kt yr−2 to 1.5 kt yr−1 in 2014. Sporadic HCFC-133a pollution events are detected in Europe from our high-resolution HCFC-133a records at three European stations, and in Asia from sam- ples collected in Taiwan. European emissions are estimated to be <0.1 kt yr−1 although emission hotspots were identi- fied in France