Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.     

On the Dependence of Prion and Amyloid Structure on the Folding Environment

Currently available analyses of amyloid proteins reveal the necessity of the existence of radical structural changes in amyloid transformation processes. The analysis carried out in this paper based on the model called fuzzy oil drop (FOD) and its modified form (FOD-M) allows quantifying the role of the environment, particularly including the aquatic environment. The starting point and basis for the present presentation is the statement about the presence of two fundamentally different methods of organizing polypeptides into ordered conformations—globular proteins and amyloids. The present study shows the source of the differences between these two paths resulting from the specificity of the external force field coming from the environment, including the aquatic and hydrophobic one. The water environment expressed in the fuzzy oil drop model using the 3D Gauss function directs the folding process towards the construction of a micelle-like system with a hydrophobic core in the central part and the exposure of polarity on the surface. The hydrophobicity distribution of membrane proteins has the opposite characteristic: Exposure of hydrophobicity at the surface of the membrane protein with an often polar center (as in the case of ion channels) is expected. The structure of most proteins is influenced by a more or less modified force field generated by water through the appropriate presence of a non-polar (membrane-like) environment. The determination of the proportion of a factor different from polar water enables the assessment of the protein status by indicating factors favoring the structure it represents.     

Structure of the cokes obtained from the group components separated from coking coal vitrites by selective thermosolvolysis

The examination of the structure of cokes obtained from extracts separated from preheated vitrites of coking coals by progressive and continuous extraction with chloroform was carried out. The structural ordering (interplanar spacing and crystallite dimensions) of the cokes depends on the rank of the parent vitrites but it does not depend on the degree of extraction. The occurrence of optical anisotropy in cokes from the extracts is connected with both the rank of the parent vitrite and the degree of extraction. In the formation of the optical anisotropic structure during the carbonization of coking coal vitrites, the part of the extract which is of small size, which partially undergoes decomposition, is an important factor.     

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature

Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors—CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (T_regs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.     

An image watermarking based on the pdf modeling and quantization effects in the wavelet domain

An image watermarking technique based on the concept of JPEG2000 algorithm is proposed. Biorthogonal wavelet 9/7 transform is used to provide a set of coefficients suitable for watermark embedding. The statistical properties of different subbands are analyzed in order to choose the number of decomposition levels and position of subbands, which will assure the best compromise between the watermark transparency and robustness. The JPEG2000 quantization is applied to avoid insignificant wavelet coefficients, while the remaining ones are used for watermarking. The optimal and blind watermark detection is based on the nonlinear score function and appropriate model of coefficients distribution. The performance of the proposed procedure is tested on examples with various images, showing robustness under different attacks, while maintaining high image quality.     

Sandwiches and milk with varying fat and sodium contents: What is the best combination?

Saltiness and fattiness were systematically varied in combinations of wheat bread (unsalted vs regular-salt), spread (none vs regular-salt and regular-fat), cheese (low-salt and low-fat vs low-fat). All possible combinations, amounting to sixteen samples of sandwich and milk, were presented to 43 subjects for ratings of pleasantness. The subjects also rated the pleasantness of individual components. The unsalted bread without spread but with low-salt, low-fat cheese and any of the milk types received the lowest hedonic ratings, whereas the regular-salt bread with spread and with any of the cheese and milk options received the highest. The pleasantness of individual components predicted the pleasantness of a combination by only 10–40% (multiple regression analysis). Thus the pleasantness of an entity depended on the pleasantness of components only to a very limited extent. The absence of major elements, such as spread on bread or the salty taste in bread, had major effects on acceptance.     

First dc Measurements of Electrons on Liquid Helium: the Helium-FET

We present the first dc-measurements on a 2-dimensional (2D) electron system floating above a liquid ⁴ He-film which covers a structured metal surface. With our arrangement of a source-, gate-, and drain-electrode a 2-dimensional charge transport is realized in analogy to a field-effect-transistor. The electrons which are moving along the x-direction due to different dc potentials are directly measured. This dc current, of the order of pA, is strongly dependent on the applied split-gate voltage. So the electrons were laterally confined to a narrow channel between the two gate electrodes. The effective width of the channel is reduced by the gate potential, so that a quasi-1D configuration can be realized. The measured electron current through the split-gate is analyzed and discussed on grounds of reduced dimensionality and 1D electron transport behaviour.     

Evaluation of functional properties of offal proteins

Evaluation of functional properties of beef heart and lip tissue proteins was based on the data obtained in the following determinations: protein extractability, fat emulsifying capacity, emulsion stability, gel forming ability, and water holding capacity after heat treatment. Beef skeletal muscles were used as the control. It was found that extractability of proteins of the raw materials was low as well as their ability to stabilize emulsions was on a low level. Proteins soluble at high ionic strength (fraction HIS) of beef heart and lip tissue emulsified 80.7 ml and 68.9 ml of oil/100 mg of protein, respectively, as compared to 106.6 ml in the control group. Analogically, protein soluble at low ionic strength (fraction LIS) emulsified 77.9 ml, 61.2 ml and 100.4 ml of oil, respectively. Emulsion stability of offal proteins appeared to be dependent on ionic strength. Generally at higher concentrations of salt their ability to stabilize emulsions was better as well as their water holding capacity increased. Their gelation properties as compared to control were also low. In each case, the functionality of cardiac proteins proved to be better than that of beef lip tissue.     

The structure and electro‐mechanical properties of novel hybrid CNT/PANI nanocomposites

Electrically conductive elastomeric nanocomposites containing carbon nanotubes (CNT) and polyaniline (PANI) are reported in the present investigation. The synthesis procedure included an in situ inverse emulsion polymerization of aniline doped with dodecylbenzene sulfonic acid (DBSA) in the presence of CNT and dissolved styrene‐isoprene‐styrene (SIS) block copolymer. The PANI synthesis step was carried out by applying ultrasonic energy. The dispersions obtained were processed by two methods: a recently developed precipitation‐filtration procedure, and a conventional drop‐cast procedure. The techniques developed resulted in homogeneous exfoliated PANI coated nanotubes within the elastomeric matrix. The presence of CNT/PANI in the SIS elastomeric matrix affects thermal, mechanical, and electrical properties of the nanocomposites. The formation of continuous three‐dimensional CNT/PANI networks prepared via the precipitation‐filtration method enhances the nanocomposite properties. Contrarily, the intermittent three‐dimensional network prepared by conventional drop‐cast method leads to inferior properties. Nanocomposites produced by both techniques are observed by HRSEM. The two processing techniques result in different structures, which affect the physical properties of the materials produced. A relatively low percolation threshold for both methods was determined. The Young's modulus of the SIS/CNT/PANI significantly increased in the presence of CNT. The precipitation‐filtration technique yields an improved nanocomposite product compared to the drop‐cast route. POLYM. COMPOS., 35:788–794, 2014. © 2013 Society of Plastics Engineers