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.     

The implications of viral reservoirs on the elite control of HIV-1 infection

The mechanisms by which a small percentage of HIV-1 infected individuals known as elite suppressors or controllers are able to control viral replication are not fully understood. Early cases of viremic control were attributed to infection with defective virus, but subsequent work has demonstrated that infection with a defective virus is not the exclusive cause of control. Replication-competent virus has been isolated from patients who control viral replication, and studies have demonstrated that evolution occurs in plasma virus but not in virus isolates from the latent reservoir. Additionally, transmission pair studies have demonstrated that patients infected with similar viruses can have dramatically different outcomes of infection. An increased understanding of the viral factors associated with control is important to understand the interplay between viral replication and host control, and has implications for the design of an effective therapeutic vaccine that can lead to a functional cure of HIV-1 infection.     

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.     

Neuroleptic-induced prolactin rise: Influence of pharmacological alterations of different neurotransmitter systems

Summary Oral administration of 2 neuroleptic drugs, haloperidol and LR511 induced in male rats a marked, dose-dependent and sustained rise of plasma prolactin.     

Uptake of ferritin from the medium byTokophrya infusionum

Summary Tokophrya infusionum, a suctorian, is deprived of a mouth opening. The uptake of ferritin from the medium is accomplished through pits, invaginations of the plasma membrane which are permanent structures. From the pits containing ferritin, flat vesicles are pinched off transporting the ferritin to the cytoplasm.Supported by grant AI-08989 US Public Health Service.The author acknowledges gratefully the excellent technical assistance of Mrs Sondra Lewengrub.     

Effect of catecholamines on ADP aggregation of rat platelets in vivo

Summary The influence of catecholamines on the platelet count was studied in an in vivo experimental model obtained with cannulation of the carotid and of the femoral vein. The i.v. infusion of epinephrine and l-norepinephrine induces a low drop in the platelet count and also potentiate aggregation by ADP.     

Seasonal variance in P system models for metapopulations

Metapopulations are ecological models describing the interactions and the behavior of populations living in fragmented habitats. In this paper, metapopulations are modelled by means of dynamical probabilistic P systems, where additional structural features have been defined (e.g., a weighted graph associated with the membrane structure and the reduction of maximal parallelism). In particular, we investigate the influence of stochastic and periodic resource feeding processes, owing to seasonal variance, on emergent metapopulation dynamics.     

Differential lethality in developmental stages ofDrosophila following X-irradiation

Summary ADrosophila melanogaster line has been treated with ionizing radiations. The dose-response relationship has been studied upon separate treatment of male and female gametes. The results show that while the total survival is similar, at different developmental stages differences can be observed between progenies from treated male and female gametes. It is suggested that developmental patterns may affect the expression of induced mutations.