CK2 signaling in androgen-dependent and -independent prostate cancer

Protein serine/threonine kinase casein kinase 2 (CK2) is a key player in cell growth and proliferation but is also a potent suppressor of apoptosis. CK2 has been found to be dysregulated in all the cancers that have been examined, including prostate cancer. Investigations of CK2 signaling in the prostate were originally initiated in this laboratory, and these studies have identified significant functional activities of CK2 in relation to normal prostate growth and to the pathobiology of androgen-dependent and -independent prostate cancer. We present a brief overview of these developments in the context of prostate biology. An important outcome of these studies is the emerging concept that CK2 can be effectively targeted for cancer therapy.     

Stable Li Metal Anode Enabled by Space Confinement and Uniform Curvature through Lithiophilic Nanotube Arrays

The application of lithium (Li) metal anodes in rechargeable batteries is primarily restricted by Li dendrite growth on the metal's surface, which leads to shortened cycle life and safety concerns. Herein, well‐spaced nanotubes with ultrauniform surface curvature are introduced as a Li metal anode structure. The ultrauniform nanotubular surface generates uniform local electric fields that evenly attract Li‐ions to the surface, thereby inducing even current density distribution. Moreover, the well‐defined nanotube spacing offers Li diffusion pathways to the electroactive areas as well as the confined spaces to host deposited Li. These structural attributes create a unique electrodeposition manner; i.e., Li metal homogenously deposits on the nanotubular wall, causing each Li nanotube to grow in circumference without obvious sign of dendritic formation. Thus, the full‐cell battery with the spaced Li nanotubes exhibits a high specific capacity of 132 mA h g^?1 at 1 C and an excellent coulombic efficiency of ≈99.85% over 400 cycles.     

Head and Neck Mycetoma: The Mycetoma Research Centre Experience

Mycetoma is a unique neglected tropical disease which is endemic in what is known as the “mycetoma belt”. The disease has many devastating impacts on patients and communities in endemic area and is characterised by massive deformity, destruction and disability. Mycetoma is commonly seen in the foot and hand and less frequent in other parts of the body. Mycetoma of the head and neck is a rarity and is associated with high morbidity and even mortality if not treated early. In this communication we report on 49 patients with head and neck mycetoma followed up at the Mycetoma Research Centre in Khartoum. Most of the reported patients had actinomycetoma and the majority were young adult males from mycetoma endemic areas in the Sudan. Most of them were students, farmers and workers. Prior to presentation the majority had long disease duration and the cause was multifactorial. Advanced disease with massive lesion, deformity and disability was the common presentation. There was no obvious history of local trauma, familial tendency or other predisposing factor identified in this group of patients. MRI and CT scan were the most accurate diagnostic tools to determine the disease extent. The treatment outcome was rather poor and characterised by low cure rate, poor outcome and high follows-up dropout. Such a gloomy outcome calls for structured and objective health education programs.     

A versatile method for functionalization and grafting of 2-hydroxyethyl cellulose (HEC) via Click chemistry

This article describes a versatile method for the modification of 2-hydroxyethyl cellulose (HEC) involving azide-alkyne cycloaddition reaction to impart neutral (ester) and ionic (carboxylic acid and 1(ry) amine) functionalities. The synthetic approach involved, first the introduction of the azide functionality to HEC and then followed by its cycloaddition reaction with several alkyne terminated compounds: namely ethyl propiolate, 5-hexynoic acid and propargyl amine. Sequential Click reactions were also demonstrated to be feasible by the successful synthesis of polydimethylsiloxane (PDMS) grafted HEC containing neutral (ester) and ionic (carboxylic acid and 1(ry) amine) functionalities. The Click chemistry was then further utilized similarly to graft poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) segments to HEC to access its hydrophobic and hydrophilic analogs, respectively. AFM analysis revealed that while HEC itself formed uniform oval features, the PLA grafted HEC exhibited a brushlike architecture. The formation of these brushlike structures suggested that the HEC backbone exhibits an extended conformation with the side chains stretched out. The resulting polymeric materials were characterized by solution and solid state (13)C NMR and FTIR spectroscopy.     

Carbonic anhydrase inhibitors. Benzenesulfonamides incorporating cyanoacrylamide moieties strongly inhibit Saccharomyces cerevisiae β-carbonic anhydrase

A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogs) were assayed as inhibitors of the β-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. Some of these compounds were low nanomolar or subnanomolar ScCA inhibitors and showed selectivity ratios in the range of 4.91–69.86 for inhibiting the yeast enzyme over the offtarget human (h) isoforms hCA I and of 6.46–13.52 for inhibiting ScCA over hCA II. The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged. Indeed, some of these sulfonamides inhibited the growth of the yeast with CC₅₀-s in the range of 0.73–6.54 μM.     

Large‐scale comparison of protein essential dynamics from molecular dynamics simulations and coarse‐grained normal mode analyses

A large‐scale comparison of essential dynamics (ED) modes from molecular dynamic simulations and normal modes from coarse‐grained normal mode methods (CGNM) was performed on a dataset of 335 proteins. As CGNM methods, the elastic network model (ENM) and the rigid cluster normal mode analysis (RCNMA) were used. Low‐frequency normal modes from ENM correlate very well with ED modes in terms of directions of motions and relative amplitudes of motions. Notably, a similar performance was found if normal modes from RCNMA were used, despite a higher level of coarse graining. On average, the space spanned by the first quarter of ENM modes describes 84% of the space spanned by the five ED modes. Furthermore, no prominent differences for ED and CGNM modes among different protein structure classes (CATH classification) were found. This demonstrates the general potential of CGNM approaches for describing intrinsic motions of proteins with little computational cost. For selected cases, CGNM modes were found to be more robust among proteins that have the same topology or are of the same homologous superfamily than ED modes. In view of recent evidence regarding evolutionary conservation of vibrational dynamics, this suggests that ED modes, in some cases, might not be representative of the underlying dynamics that are characteristic of a whole family, probably due to insufficient sampling of some of the family members by MD. Proteins 2010. © 2010 Wiley‐Liss, Inc.     

Identification of Residues Surrounding the Active Site of Type A Botulinum Neurotoxin Important for Substrate Recognition and Catalytic Activity

Type A botulinum neurotoxin is one of the most lethal of the seven serotypes and is increasingly used as a therapeutic agent in neuromuscular dysfunctions. Its toxic function is related to zinc-endopeptidase activity of the N-terminal light chain (LC) on synaptosome-associated protein-25 kDa (SNAP-25) of the SNARE complex. To understand the determinants of substrate specificity and assist the development of strategies for effective inhibitors, we used site-directed mutagenesis to investigate the effects of 13 polar residues of the LC on substrate binding and catalysis. Selection of the residues for mutation was based on a computational analysis of the three-dimensional structure of the LC modeled with a 17-residue substrate fragment of SNAP-25. Steady-state kinetic parameters for proteolysis of the substrate fragment were determined for a set of 16 single mutants. Of the mutated residues non-conserved among the serotypes, replacement of Arg-230 and Asp-369 by polar or apolar residues resulted in drastic lowering of the catalytic rate constant (k _cat), but had less effect on substrate affinity (K _m). Substitution of Arg-230 with Lys decreased the catalytic efficiency (k _cat/K _m) by 50-fold, whereas replacement by Leu yielded an inactive protein. Removal of the electrostatic charge at Asp-369 by mutation to Asn resulted in 140-fold decrease in k _cat/K _m. Replacement of other variable residues surrounding the catalytic cleft (Glu-54, Glu-63, Asn-66, Asp-130, Asn-161, Glu-163, Glu-170, Glu-256), had only marginal effect on decreasing the catalytic efficiency, but unexpectedly the substitution of Lys-165 with Leu resulted in fourfold increase in k _cat/K _m. For comparison purposes, two conserved residues Arg-362 and Tyr-365 were investigated with substitutions of Leu and Phe, respectively, and their catalytic efficiency decreased 140- and 10-fold, respectively, whereas substitution of the tyrosine ring with Asn abolished activity. The altered catalytic efficiencies of the mutants were not due to any significant changes in secondary or tertiary structures, or in zinc content and thermal stability. We suggest that, despite the large minimal substrate size for catalysis, only a few non-conserved residues surrounding the active site are important to render the LC competent for catalysis or provide conformational selection of the substrate.     

Which diameter and angle rule provides optimal flow patterns in a coronary bifurcation?

The branching angle and diameter ratio in epicardial coronary artery bifurcations are two important determinants of atherogenesis. Murray's cubed diameter law and bifurcation angle have been assumed to yield optimal flows through a bifurcation. In contrast, we have recently shown a 7/3 diameter law (HK diameter model), based on minimum energy hypothesis in an entire tree structure. Here, we derive a bifurcation angle rule corresponding to the HK diameter model and critically evaluate the streamline flow through HK and Murray-type bifurcations. The bifurcations from coronary casts were found to obey the HK diameter model and angle rule much more than Murray's model. A finite element model was used to investigate flow patterns for coronary artery bifurcations of various types. The inlet velocity and pressure boundary conditions were measured by ComboWire. Y-bifurcation of Murray type decreased wall shear stress-WSS (10%-40%) and created an increased oscillatory shear index-OSI in atherosclerosis-prone regions as compared with HK-type bifurcations. The HK-type bifurcations were found to have more optimal flow patterns (i.e., higher WSS and lower OSI) than Murray-type bifurcations which have been traditionally believed to be optimized. This study has implications for changes in bifurcation angles and diameters in percutaneous coronary intervention.     

Kidney Function,Endothelial Activation and Atherosclerosis in Black and White Africans with Rheumatoid Arthritis

Objective

To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA).

Methods

We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients.

Results

The CKD-EPI eGFR was <90 ml/min/1.73m² in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval) = 2.19 (1.28–3.75), p = 0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p = 0.3), whereas the respective relationship was significant or borderline significant (p = 0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold.

Conclusion

Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients.