Cell-permeable dual inhibitors of protein kinases CK2 and PIM-1: structural features and pharmacological potential

It has been proposed that dual inhibitors of protein kinases CK2 and PIM-1 are tools particularly valuable to induce apoptosis of cancer cells, a property, however, implying cell permeability, which is lacking in the case of selective CK2/PIM-1 inhibitors developed so far. To fill this gap, we have derivatized the scaffold of the promiscuous CK2 inhibitor TBI with a deoxyribose moiety, generating TDB, a selective, cell-permeable inhibitor of CK2 and PIM-1. Here, we shed light on the structural features underlying the potency and narrow selectivity of TDB by exploiting a number of TDB analogs and by solving the 3D structure of the TDB/CK2 complex at 1.25?Å resolution, one of the highest reported so far for this kinase. We also show that the cytotoxic efficacy of TDB is almost entirely due to apoptosis, is accompanied by parallel inhibition of cellular CK2 and PIM-1, and is superior to both those observed combining individual inhibitors of CK2 and PIM-1 and by treating cells with the CK2 inhibitor CX4945. These data, in conjunction with the observations that cancer cells are more susceptible than non-cancer cells to TDB and that such a sensitivity is maintained in a multi-drug resistance background, highlight the pharmacological potential of this compound.     

Serotype-independent pneumococcal vaccines

Streptococcus pneumoniae remains an important cause of disease with high mortality and morbidity, especially in children and in the elderly. The widespread use of the polysaccharide conjugate vaccines in some countries has led to a significant decrease in invasive disease caused by vaccine serotypes, but an increase in disease caused by non-vaccine serotypes has impacted on the overall efficacy of these vaccines on pneumococcal disease. The obvious solution to overcome such shortcomings would be the development of new formulations that provide serotype-independent immunity. This review focuses on the most promising approaches, including protein antigens, whole cell pneumococcal vaccines, and recombinant bacteria expressing pneumococcal antigens. The protective capacity of these vaccine candidates against the different stages of pneumococcal infection, including colonization, mucosal disease, and invasive disease in animal models is reviewed. Some of the human trials that have already been performed or that are currently ongoing are presented. Finally, the feasibility and the possible shortcomings of these candidates in relation to an ideal vaccine against pneumococcal infections are discussed.     

Training Load Monitoring Algorithms on Highly Sub-Metered Home Electricity Consumption Data

The growing interest in energy-efficient buildings is driving changes in investment, design, and occupant behavior. To better focus cost and resource conservation efforts, electricity consumption feedback can be used to provide motivation, guidance, and verification. Disaggregating by end-use helps both consumers and producers to identify targets for conservation. While hardware-based sub-metering is costly and labor-intensive, non-intrusive load monitoring (NILM) is capable of gathering detailed energy-use data with minimal equipment cost and installation time. However, variations in measurements between metering devices complicate the process of compiling the necessary appliance profiles. Future work involves the devel-opment of NILM algorithms using sensor fusion and detailed appliance-level data gathered from a highly-sensed house currently being constructed near Pittsburgh, Pennsylvania.     

A Dynamic Model Selection Procedure to Forecast Using Multi-Process Models

Multi-process models are particularly useful when observations appear extreme relative to their forecasts, because they allow for explanations of any behaviour of a time series, considering more generating sources simultaneously. In this paper, the multi-process approach is extended by developing a dynamic procedure to assess the weights of the various sources, alias the prior probabilities of the rival models, that compete in the collection to make forecasts. The new criterion helps the forecasting system to learn about the most plausible scenarios for the time series, considering all the combinations of consecutive models to be a function of the magnitude of the one-step-ahead forecast error. Throughout the paper, the different treatments of outliers and structural changes are highlighted using the concepts of robustness and sensitivity. Finally, the dynamic selection procedure is tested on the CP6 dataset, showing an effective improvement in the overall predictive ability of multi-process models whenever anomalous observations occur. © 1997 John Wiley & Sons, Ltd.     

Imagery Enhancement and Interpretation for Remote Visual Inspection of Aging Civil Infrastructure

In this paper, we describe an image enhancement and interpretation methodology to enhance and recognize surface defects and critical patterns from remote imagery of sewer pipeline inspection. The objective is to provide inspectors and professionals with better tools to allow them to examine the imagery for condition assessment. We present initial results of a collaboration with a robotic company through a case study on computer-assisted processing and interpretation of sewer pipeline inspection imagery. In the mean time, the described enhancement and interpretation methodology can also be applied to sewer pipeline condition assessment in an offline mode, where this methodology can support professionals’ examination of acquired sewer condition imagery.     

Expression of the Stp1 LMW-PTP and inhibition of protein CK2 display a cooperative effect on immunophilin Fpr3 tyrosine phosphorylation and <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis> growth

Although the yeast genome does not encode bona fide protein tyrosine kinases, tyrosine-phosphorylated proteins are numerous, suggesting that besides dual-specificity kinases, some Ser/Thr kinases are also committed to tyrosine phosphorylation in Saccharomyces cerevisiae. Here we show that blockage of the highly pleiotropic Ser/Thr kinase CK2 with a specific inhibitor synergizes with the overexpression of Stp1 low-molecular-weight protein tyrosine phosphatase (PTP) in inducing a severe growth-defective phenotype, consistent with a prominent role for CK2 in tyrosine phosphorylation in yeast. We also present in vivo evidence that immunophilin Fpr3, the only tyrosine-phosphorylated CK2 substrate recognized so far, interacts with and is dephosphorylated by Spt1. These data disclose a functional correlation between CK2 and LMW-PTPs, and suggest that reversible phosphorylation of Fpr3 plays a role in the regulation of growth rate and budding in S. cerevisiae.Received 15 January 2004; received after revision 20 February 2004; accepted 4 March 2004     

The Definitions of Fundamental Geometric Entities Contained in Book I of Euclids Elements

OElig;he thesis is sustained that the definitions of fundamental geometric entities which open Euclids Elements actually are excerpts from the Definitions by Heron of Alexandria, interpolated in late antiquity into Euclids treatise. As a consequence, one of the main bases of the traditional Platonist interpretation of Euclid is refuted. Arguments about the constructivist nature of Euclids mathematical philosophy are given. (Received June 6, 1997)     

Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

Isoform specific phosphorylation of p53 by protein kinase CK1

The ability of three isoforms of protein kinase CK1 (α, γ₁, and δ) to phosphorylate the N-terminal region of p53 has been assessed using either recombinant p53 or a synthetic peptide reproducing its 1–28 sequence. Both substrates are readily phosphoylated by CK1δ and CK1α, but not by the γ isoform. Affinity of full size p53 for CK1 is 3 orders of magnitude higher than that of its N-terminal peptide (K _m 0.82 μM vs 1.51 mM). The preferred target is S20, whose phosphorylation critically relies on E17, while S6 is unaffected despite displaying the same consensus (E-x-x-S). Our data support the concept that non-primed phosphorylation of p53 by CK1 is an isoform-specific reaction preferentially affecting S20 by a mechanism which is grounded both on a local consensus and on a remote docking site mapped to the K²²¹RQK²²⁴ loop according to modeling and mutational analysis.