Regulation of the specific and nonspecific ion conductivity of mitochondria by adenine nucleotide carriers]

The functioning of the adenine nucleotide carrier as a regulated pore which, depending on incubation conditions, operates as either a specific conductivity channel for H+ and K+ ions, or a nonspecific channel for low molecular weight metabolites, is reviewed. Both specific and nonspecific conductivities over this specific channel are controlled by the conformational state of the carrier protein molecule. The conformational states of the ATP/ADP-carrier alter by the specific effect of adenine nucleotides, ATP/ADP transport inhibitors, Ca2+ ions, medium tonicity, and energization of mitochondria. The transition of the ATP/ADP-carrier to the conformational state characterized by nonspecific conductivity is inhibited by cyclosporin A. The roles of the adenine nucleotide carrier in the realization of effects of Ca(2+)-mobilizing hormones and glucagon during mitochondrial function are discussed.     

Coevolution of virulence and immunosuppression in multiple infections

Many components of host–parasite interactions have been shown to affect the way virulence (i.e. parasite‐induced harm to the host) evolves. However, coevolution of multiple parasite traits is often neglected. We explore how an immunosuppressive adaptation of parasites affects and coevolves with virulence in multiple infections. Applying the adaptive dynamics framework to epidemiological models with coinfection, we show that immunosuppression is a double‐edged sword for the evolution of virulence. On one hand, it amplifies the adaptive benefit of virulence by increasing the abundance of coinfections through epidemiological feedbacks. On the other hand, immunosuppression hinders host recovery, prolonging the duration of infection and elevating the cost of killing the host (as more opportunities for transmission will be forgone if the host dies). The balance between the cost and benefit of immunosuppression varies across different background mortality rates of hosts. In addition, we find that immunosuppression evolution is influenced considerably by the precise trade‐off shape determining the effect of immunosuppression on host recovery and susceptibility to further infection. These results demonstrate that the evolution of virulence is shaped by immunosuppression while highlighting that the evolution of immune evasion mechanisms deserves further research attention.     

Leukocytolysis and phagocytosis under hyperosmotic conditions]

PAN and leukocytolysis were measured in dog blood placed in hypo- and hypertonic solutions of glycerin and glucose (1:10). It was found that leukocytolytic activity of the substances depends on equimolar concentrations of nonelectrolytes. It is more pronounced in hypo- than in hypertonic conditions. Glycerin is 3-5-times more active than glucose. In concentrations 2.0 M for glycerin and 0.5 M for glucose leukocytolysis is less active. Mononuclears are more resistant than neutrophils in strong solutions. PAN increased by 11-16% in hypotonic solutions. Strong glycerin solutions reduce PAN less than glucose which stimulates the digestive activity. The results can be of use in specific leukolysis tests to diagnose drug allergy.     

Change in the activity of specific and nonspecific immunity mechanisms in vitamin B1 deficiency]

The effect of thiamin deficiency on the immune response and activity of some mechanisms of natural immunity was studied in experimental mature rats. Thiamin deficiency was simulated by a single injection of hydroxythiamin (thiamin antagonists). Hydroxythiamin markedly decreased the complement activity, phagocytic activity of peripheral blood leucocytes, serum bactericidal activity as well as antibody production in response to sheep red blood cells. On the contrary, lysozyme activity increased. Vitamin B1 deficiency reduced 14C-leucine incorporation activity in the liver proteins.     

Mechanisms of development of immunosuppression during Trypanosoma infections

Acute infection with Trypanosoma cruzi or its African relatives, including T. brucei rhodesiense, T. b. gambiense, T. b. brucei and T. congolense, is frequently accompanied by manifestations of immunological dysfunction. Initially investigators catalogued the ensuing immunologic alterations and identified a number of modifications in lymphoid or accessory cell properties. More recently, the emphasis has switched towards the molecular underpinnings of immunosuppression in these infections. In this article, Marcelo Sztein and Felipe Kierszenboum focus on recent progress made in the quest to delineate the mechanisms behind altered lymphocyte functions in tryponosomal infections, point out particular and common features of immunosuppression induced by T. cruzi and African trypanosomes, and outline possible directions for future research.     

Recognition of specific and nonspecific DNA by human lactoferrin

The general principles of recognition of nucleic acids by proteins are among the most exciting problems of molecular biology. Human lactoferrin (LF) is a remarkable protein possessing many independent biological functions, including interaction with DNA. In human milk, LF is a major DNase featuring two DNA‐binding sites with different affinities for DNA. The mechanism of DNA recognition by LF was studied here for the first time. Electrophoretic mobility shift assay and fluorescence measurements were used to probe for interactions of the high‐affinity DNA‐binding site of LF with a series of model‐specific and nonspecific DNA ligands, and the structural determinants of DNA recognition by LF were characterized quantitatively. The minimal ligands for this binding site were orthophosphate (K_i = 5 mM), deoxyribose 5'‐phosphate (K_i = 3 mM), and different dNMPs (K_i = 0.56–1.6 mM). LF interacted additionally with 9–12 nucleotides or nucleotide pairs of single‐ and double‐stranded ribo‐ and deoxyribooligonucleotides of different lengths and sequences, mainly through weak additive contacts with internucleoside phosphate groups. Such nonspecific interactions of LF with noncognate single‐ and double‐stranded d(pN)₁₀ provided ~6 to ~7.5 orders of magnitude of the enzyme affinity for any DNA. This corresponds to the Gibbs free energy of binding (ΔG⁰) of ?8.5 to ?10.0 kcal/mol. Formation of specific contacts between the LF and its cognate DNA results in an increase of the DNA affinity for the enzyme by approximately 1 order of magnitude (K_d = 10 nM; ΔG⁰ ≈ ?11.1 kcal/mol). A general function for the LF affinity for nonspecific d(pN)_n of different sequences and lengths was obtained, giving the K_d values comparable with the experimentally measured ones. A thermodynamic model was constructed to describe the interactions of LF with DNA. Copyright © 2013 John Wiley & Sons, Ltd.     

Conversion of specific to nonspecific cytotoxic T lymphocytes

The type of cytotoxic T lymphocyte (CTL) generated during a mixed leukocyte culture has been shown to depend on the purity of interleukin 2 (IL 2) used to stimulate growth. Antigen-specific CTL requiring both antigen and IL 2 to proliferate or express cytotoxicity (designated Type I in this work) are generated and maintained with highly purified IL 2. In the presence of IL 2 alone, they persist in a quiescent, noncytotoxic state, and on its removal they rapidly die. A second type of CTL (Type II), of nonspecific cytotoxicity, and dependent only on IL 2 for growth, is generated by exposure to an impure lymphokine preparation containing IL 2. Type I cells are T lymphocytes which are nongranular and nonadherent, whereas Type II cells are larger, adhere to plastic, and contain many granules. Cloned Type I cells are converted to Type II under three conditions: by low levels of IL 2 in the presence of a crude lymphokine preparation; by high levels of IL 2 in the presence of antigen; or by high levels of IL 2 in the presence of the phorbol diester PMA. Conversion results from an effect of the growth conditions on individual cells, and not from selection of a minor population.     

Distinguishing specific and nonspecific interdomain interactions in multidomain proteins

Multidomain proteins account for over two-thirds of the eukaryotic genome. Although there have been extensive studies into the biophysical properties of isolated domains, few have investigated how the domains interact. Spectrin is a well-characterized multidomain protein with domains linked in tandem array by contiguous helices. Several of these domains have been shown to be stabilized by their neighbors. Until now, this stabilization has been attributed to specific interactions between the natural neighbors, however we have recently observed that nonnatural neighboring domains can also induce a significant amount of stabilization. Here we investigate this nonnative stabilizing effect. We created spectrin-titin domain pairs of both spectrin R16 and R17 with a single titin I27 domain at either the N- or the C-terminus and found that spectrin domains are significantly stabilized, through slowed unfolding, by nonnative interactions at the C-terminus only. Of particular importance, we show that specific interactions between natural folded neighbors at either terminus confer even greater stability by additionally increasing the folding rate constants. We demonstrate that it is possible to distinguish between natural stabilizing interactions and nonspecific stabilizing effects through examination of the kinetics of well chosen mutant proteins. This work adds to the complexity of studying multidomain proteins.     

Factors of transmission of salmonella infections under their sporadic spread conditions

Epidemiological and microbiological studies carried out with the application of the principles of epidemiological observation permitted to ascertain the principal edpiemiological regularities of salmonelloses in one of the Moscow dictricts, to reveal the main factors determining these regularities, and the definite ways and conditions of their realization. Factual data indicating that there were no principal differences in the character of development of the epidemic process in case of the so called sporadic salmonelloses and salmonelloses occurring by the type of food poisoning foci were obtained.