According to the “thermodynamic hypothesis”, the sequence of a biological macromolecule defines its folded, active structure as a global energy minimum on the folding landscape.1,2 But the enormous complexity of folding landscapes of large macromolecules raises a question: Is there indeed a unique global energy minimum corresponding to a unique native conformation, or are there deep local minima corresponding to alternative active conformations?3 Folding of many proteins is well described by two-state models, leading to highly simplified representations of protein folding landscapes with a single native conformation.4,5 Nevertheless, accumulating experimental evidence suggests a more complex topology of folding landscapes with multiple active conformations that can take seconds or longer to interconvert.6,7,8 Here we employ single molecule experiments to demonstrate that an RNA enzyme folds into multiple distinct native states that interconvert much slower than the time scale of catalysis. These data demonstrate that the severe ruggedness of RNA folding landscapes extends into conformational space occupied by native conformations.
A clinical prototype of the laser optoacoustic imaging system (LOIS) was employed for breast cancer detection and localization in patients with confirmed breast cancer and scheduled for radical mastectomy. The prototype LOIS used a single optical fiber for delivery of laser pulses, an arc shaped 32-element PVDF transducer array for ultrawide-band piezoelectric detection of optoacoustic signals and a single-channel data acquisition card for signal processing. The resonance ultrasound frequency of the 1 10 im PVDF film was outside detectable range of ultrasound. Spatial resolution of the transducer array was slightly better than 1mm in radial direction and slightly worse than 1 mm in lateral direction. The system was optimized for contrast and sensitivity. Data acquisition, signal conditioning and image processing were significantly improved and optimized resulting in reduced image frame rate of 2 seconds employing 700 MHz Aphion processor. The computer code for digital signal processing employed band-pass hyper-Gaussian filtering and denoising. An automatic recognition of the optoacoustic signal detected from the irradiated surface was implemented in order to visualize the breast surface and improve the accuracy of tumor localization. Radial back-projection algorithm was employed adopting combination of integration along spherical wavefronts and integration along planar wavefronts (as in Radon transform) for image reconstruction. The system performance was evaluated initially in breast tissue-like phantoms with embedded blood vessels. Clinical studies in breast cancer patients scheduled for surgical mastectomy were performed and compared with xray radiography, ultrasound and pathology reports.
Nanoscale size materials, displaying environmentally responsive behavior, are of special interest for various applications, including drug delivery. This work explores the effects of environmental parameters (pH, concentration, and chemical nature of low molecular weight salts) on self-assembly and physicochemical properties of block ionomer complexes (BIC). BIC are synthesized by reacting block ionomer (PEO-b-PMA) and oppositely charged surfactant (hexadecyltrimethylammonium bromide). The resulted BIC form stable aqueous dispersions at any ionomer/surfactant ratio (particle size in the 60-90 nm range). Decrease of the ionization degree of the PMA block upon decrease of pH causes elevation of particle size at pH < 5.5 followed by formation of large aggregates at pH < 4. Increase of pH causes a decrease of the particle size. Addition of low molecular weight salts leads to disintegration of BIC at a specific salt concentration termed the "critical salt concentration" or csc. The csc values strongly depend on the nature of the salt. For cations csc increases in the order K + ≈ Li + ≈ Na + > N(CH3)4 + . For anions it increases in the order I -> Br -> Cl -> AcO -> F -. Such behavior is explained by the contribution of binding of counterions with PMA segments and surfactant cations. The disintegration process is reversible, as BIC particles reconstitute as the salt concentration decreases.
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