Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases

The papain-family cathepsins are cysteine proteases that are emerging as promising therapeutic targets for a number of human disease conditions ranging from osteoporosis to cancer. Relatively few selective inhibitors for this family exist, and the in vivo selectivity of most existing compounds is unclear. We present here the synthesis of focused libraries of epoxysuccinyl-based inhibitors and their screening in crude tissue extracts. We identified a number of potent inhibitors that display selectivity for endogenous cathepsin targets both in vitro and in vivo. Importantly, the selectivity patterns observed in crude extracts were generally retained in vivo, as assessed by active-site labeling of tissues from treated animals. Overall, this study identifies several important compound classes and highlights the use of activity-based probes to assess pharmacodynamic properties of small-molecule inhibitors in vivo.     

Analogy between unconventional superconductivity and unconventional states of liquid crystals

An analogy is stressed between the order-parameter symmetries of the two-dimensional d-pairing wave superconductors and of liquid-crystal mesophases formed from achiral bent-shaped molecules. It leads to a definition of a class of liquid-crystal states which are the analogs of the unconventional superconducting states, and are characterized by a loss of discrete symmetry operations of the parent state.     

Critical petermann K factor for intensity noise squeezing

We investigate the impact of the Petermann-excess-noise factor K>/=1 on the possibility of intensity noise squeezing of laser light below the standard quantum limit. Using an N-mode model, we show that squeezing is limited to a floor level of 2(K-1) times the shot noise limit. Thus, even a modest Petermann factor significantly impedes squeezing, which becomes impossible when K>/=1.5. This appears as a serious limitation for obtaining sub-shot-noise light from practical semiconductor lasers. We present experimental evidence for our theory.     

Search for isovector giant monopole resonances via the Pb(3He,tp) reaction

The (nat)Pb(3He,tp) reaction at E(3He) = 177 MeV was studied to identify 2Planck's over 2piomega isovector monopole strength in Bi isotopes. Monopole strength was found in the region -45相似文献   

Creatine kinase B deficient neurons exhibit an increased fraction of motile mitochondria

Background  

Neurons require an elaborate system of intracellular transport to distribute cargo throughout axonal and dendritic projections. Active anterograde and retrograde transport of mitochondria serves in local energy distribution, but at the same time also requires input of ATP. Here we studied whether brain-type creatine kinase (CK-B), a key enzyme for high-energy phosphoryl transfer between ATP and CrP in brain, has an intermediary role in the reciprocal coordination between mitochondrial motility and energy distribution. Therefore, we analysed the impact of brain-type creatine kinase (CK-B) deficiency on transport activity and velocity of mitochondria in primary murine neurons and made a comparison to the fate of amyloid precursor protein (APP) cargo in these cells, using live cell imaging.