Influence of the length of the phosphate chain in mRNA 5' cap analogues on their interaction with eukaryotic initiation factor 4E

The recognition of the 5'mRNA cap structure m7G(5')ppp(5')N by one of the components of the initiation translation machinery, the eIF4E factor, plays a pivotal role in regulation of the protein synthesis. In the present study we have shown two opposing roles of the cap phosphate chain in the specific eIF4E-cap interaction. The extension of the phosphate chain enhances the binding of the cap to the unphosphorylated eIF4E but destabilises the eIF4E-cap complex in case of the phosphorylated protein.     

Binding studies of eukaryotic initiation factor eIF4E with novel mRNA dinucleotide cap analogues

Studies on the interaction of the murine translation initiation factor 4E with two new-synthesized cap-analogues, modified at C2' of 7-methylguanosine, have been performed by means of the fluorescence titration method. No difference in the binding affinity for eIF4E was observed compared with the "anti reversed" cap analogues, possessing the analogous modifications at C3'. Potential significance of the novel caps as research tools for examination of the nuclear cap binding complex CBC80/20 has been discussed.     

Interaction between yeast eukaryotic initiation factor eIF4E and mRNA 5' cap analogues differs from that for murine eIF4E

Measurements of interaction of 7-methyl-GTP eIF4E from S. cerevisiae were performed by means of two methods: Isothermal Titration Calorimetry (ITC) and fluorescence titration. The equilibrium association constants (Kas) derived from the two methods show significantly different affinity of yeast eIF4E for the mRNA 5' cap than those of the murine and human proteins. The observed differences in the Kas values and the enthalpy changes of the association (deltaH(o)) suggest some dissimilarity in the mode of binding and stabilization of cap in the complexes with eIF4E from various sources.     

Structure-activity relationships of novel anti-malarial agents: part 5. N-(4-acylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides

We have developed the [5-(4-nitrophenyl)-2-furyl]acrylic acid substituted benzophenone 4g as a novel lead for anti-malarial agents. Here, we demonstrated that the acyl residue at the 2-amino group of the benzophenone core structure has to be a phenylacetic acid substructure substituted in its para-position with methyl or other substituents of similar size. The trifluoromethyl substituted derivative displayed an IC(50) of 47 nM against the multi-drug resistant Plasmodium falciparum strain Dd2.     

Comparison of life-history traits of the two male morphs of the bulb mite, Rhizoglyphus robini

Two basic male morphs occur in several species of the family Acaridae: heteromorphic fighters, possessing a thickened and sharply terminated third pair of legs, and homeomorphic males with unmodified legs. We compared major life-history traits of the two morphs in the bulb mite, Rhizoglyphus robini. We found no significant differences in development time or virility, but homeomorphic males lived 23% longer than heteromorphs. We discuss the possibility that the trade-off between longevity and adaptation for fighting maintains genetic variation for the male morph in the studied species.     

Damped sinusoidal function to model acute irradiation in radiotherapy patients

In the paper, we suggest a damped sinusoidal function be used to model a regenerative response of mucosa in time after the radiotherapy treatment. The medical history of 389 RT patients irradiated within the years 1994–2000 at the Radiotherapy Department, Cancer Center, Maria Sk?odowska-Curie Memorial Institute of Oncology, Gliwice, Poland, was taken into account. In the analyzed group of patients, the number of observations of a single patient ranged from 2 to 25 (mean = 8.3, median = 8) with severity determined by use of Dische's scores from 0 to 24 (mean = 7.4, median = 7). Statistical modeling of radiation-induced mucositis was performed for five groups of patients irradiated within the following radiotherapy schedules: CAIR, CB, Manchester, CHA–CHA, and Conventional. All of the regression parameters of the assumed model, i.e. amplitude, damping coefficient, angular frequency, phase of component, and offset, estimated in the analysis were statistically significant (p-value < 0.05) for the radiotherapy schedules. The model was validated using a non-oscillatory function. Following goodness-of-fit statistics, the damped sinusoidal function fits the data better than the non-oscillatory damped function. Model curves for harmonic characteristics with confidence intervals were plotted separately for each of the RT schedules and together in a combined design. The suggested model might be helpful in the numeric evaluation of the RT toxicity in the groups of patients under analysis as it allows for practical comparisons and treatment optimization. A statistical approach is also briefly described in the paper.     

Genetic analysis of candidate genes modifying the age-at-onset in Huntington’s disease

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington’s disease (HD) and determines 42–73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .     

Electrostatic potentials in membrane systems

A membrane with an arbitrary distribution of fixed charges inside and on its surfaces is considered. A procedure for calculating the local electrostatic potential at an arbitrary point of the system is described and its validity discussed. This procedure is based on the linearization of the 3-dimensional Poisson-Boltzmann equation around an exact 1-dimensional solution.     

The human immunodeficiency virus type 1 nef gene can to a large extent replace simian immunodeficiency virus nef in vivo.

The nef gene of the pathogenic simian immunodeficiency virus (SIV) 239 clone was replaced with primary human immunodeficiency virus type 1 (HIV-1) nef alleles to investigate whether HIV-1 Nef can substitute for SIV Nef in vivo. Initially, two rhesus macaques were infected with the chimeric viruses (Nef-SHIVs). Most of the nef alleles obtained from both animals predicted intact open reading frames. Furthermore, forms containing upstream nucleotide substitutions that enhanced expression of the inserted gene became predominant. One animal maintained high viral loads and slowly progressed to immunodeficiency. nef long terminal repeat sequences amplified from this animal were used to generate a second generation of Nef-SHIVs. Two macaques, which were subsequently infected with a mixture of cloned chimeric viruses, showed high viral loads and progressed to fatal immunodeficiency. Five macaques received a single molecular clone, named SHIV-40K6. The SHIV-40K6 nef allele was active in CD4 and class I major histocompatibility complex downregulation and enhanced viral infectivity and replication. Notably, all of the macaques inoculated with SHIV-40K6 showed high levels of viral replication early in infection. During later stages, however, the course of infection was variable. Three animals maintained high viral loads and developed immunodeficiency. Of the remaining two macaques, which showed decreasing viral loads after the acute phase of infection, only one efficiently controlled viral replication and remained asymptomatic during 1.5 years of follow-up. The other animal showed an increasing viral load and developed signs of progressive infection during later stages. Our data demonstrate that HIV-1 nef can, to a large extent, functionally replace SIVmac nef in vivo.