Role of the Yes and Csk tyrosine kinases in the development of a pathological state in the human retina

Amplification and a cloning of fragments of genes of human retina tyrosine kinases, the nucleotide sequences of which feature a high homology to the gene families of the Yes and Csk tyrosine kinases, and a cloning of the complete coding sequence of the cDNA of the Csk tyrosine kinase gene of the human lymphocytes have been carried out. It has been established that this sequence contains 1,624 bp and encodes a protein that, with a 99% homology, corresponds to the human tyrosine kinase. A comparative analysis of the nucleotide sequences of the full-size cDNA of the Csk tyrosine kinase of the lymphocytes of healthy donors and of patients with an eye choroidal melanoma has shown that a risk of development of an eye choroidal melanoma can be estimated by the frequency of occurrence of a mutant allele in the 10th exon.     

A genetic component of extinction risk in mammals

Genetic factors may play an important role in species extinction but their actual effect remains poorly understood, particularly because of a strong and potentially masking effect expected from ecological traits. We investigated the role of genetics in mammal extinction taking both ecological and genetic factors into account. As a proxy for the role of genetics we used the ratio of the rates of nonsynonymous (amino acid changing) to synonymous (leaving the amino acid unchanged) nucleotide substitutions, K_a / K_s. Because most nonsynonymous substitutions are likely to be slightly deleterious and thus selected against, this ratio is a measure of the inefficiency of selection: if large (but less than 1), it implies a low efficiency of selection against nonsynonymous mutations. As a result, nonsynonymous mutations may accumulate and thus contribute to extinction. As a proxy for the role of ecology we used body mass W, with which most extinction‐related ecological traits strongly correlate. As a measure of extinction risk we used species’ affiliation with the five levels of extinction threat according to the IUCN Red List of Threatened Species. We calculated K_a / K_s for mitochondrial protein‐coding genes of 211 mammalian species, each of which was characterized by body mass and the level of threat. Using logistic regression analysis, we then constructed a set of logistic regression models of extinction risk on ln(K_a / K_s) and lnW. We found that K_a / K_s and body mass are responsible for a 38% and a 62% increase in extinction risk, respectively. Given that the standard error of these values is 13%, the contribution of genetic factors to extinction risk in mammals is estimated to be one‐quarter to one‐half of the total of ecological and genetic effects. We conclude that the effect of genetics on extinction is significant, though it is almost certainly smaller than the effect of ecological traits. Synthesis Mutation provides the material for evolution. However, most mutations that play a role in evolution are slightly deleterious and thus may contribute to extinction. We assess the role of mitochondrial DNA mutations in mammalian extinction risk and find it to be one‐quarter to one‐half of the total of mutation and body mass effects, where body mass represents an integral measure of extinction‐related ecological traits. Genetic factors may be all the more important, because ecological traits associated with large body mass would both promote and protect from extinction, while mutation accumulation caused by low effective population size seems to have no counterbalance.     

Catalytic antibodies from HIV-infected patients specifically hydrolyzing viral integrase suppress the enzyme catalytic activities

Human immunodeficiency virus type 1 integrase (IN) catalyzes integration of a DNA copy of the viral genome into the host genome. It was shown previously that IN preincubation with various oligodeoxynucleotides (ODNs) induces formation of dimers and oligomers of different gyration radii; only specific ODNs stimulate the formation of catalytically active dimers. Here we have shown that preincubation of IN with specific and nonspecific ODNs leads to a significant and comparable decrease in its hydrolysis by chymotrypsin, while nonspecific ODNs protect the enzyme from the hydrolysis by trypsin worse than specific ODNs; all ODNs had little effect on the IN hydrolysis by proteinase K. In contrast to canonical proteweases, IgGs from HIV‐infected patients specifically hydrolyze only IN. While d(pT)_n markedly decreased the IgG‐dependent hydrolysis of IN, d(pA)_n and d(pA)_n?d(pT)_n demonstrated no detectable protective effect. The best protection from the hydrolysis by IgGs was observed for specific single‐ and especially double‐stranded ODNs. Although IN was considerably protected by specific ODNs, proteolytic IgGs and IgMs significantly suppressed both 3′‐processing and integration reaction catalyzed by IN. Since anti‐IN IgGs and IgMs can efficiently hydrolyze IN, a positive role of abzymes in counteracting the infection cannot be excluded. Copyright © 2011 John Wiley & Sons, Ltd.     

Genetic diversity of wild reindeer (<Emphasis Type="Italic">Rangifer tarandus</Emphasis>) of Taimyr: Analysis of polymorphism of the control region of mitochondrial DNA

Based on an analysis of the polymorphism of nucleotide sequences (n = 111) of the mtDNA control region (left domain), the genetic diversity of the largest population of wild reindeer Rangifer tarandus in Eurasia, which inhabits Taimyr peninsula, was studied. High levels of haplotype (H) and nucleotide (π) diversity (0.987 and 0.018, respectively) were revealed, which indicate the long existence and the sufficiently stable growth of this population. The absence of long periods of abrupt decrease in the number of the Taimyr wild reindeer population and/or facts of formation of its genetic diversity as a result of mixing of genetically distant conspecific populations is supported by the data on the pattern of mismatch distributions and the topology of the phylogenetic tree. The low level of genetic differences between reindeer from the western, central, and eastern groups reflects their common origin and close relationship.     

An unusual presentation of a malignant jejunal tumor and a different management strategy

BACKGROUND: Malignant small bowel tumors are very rare and leiomyosarcoma accounts for less than 15% of the cases. Management of these tumors is challenging in view of nonspecific symptoms, unusual presentation and high incidence of metastasis. In this case report, an unusual presentation of jejunal sarcoma and management of liver metastasis with radiofrequency ablation (RFA) is discussed. CASE PRESENTATION: A 45-year-old male presented with anemia and features of small bowel obstruction. Operative findings revealed a mass lesion in jejunum with intussusception of proximal loop. Resection of bowel mass was performed. Histopathological findings were suggestive of leiomyosarcoma. After 3-years of follow-up, the patient developed recurrence in infracolic omentum and a liver metastasis. The omental mass was resected and liver lesion was managed with radiofrequency ablation. CONCLUSION: Jejunal leiomyosarcoma is a rare variety of malignant small bowel tumor and a clinical presentation with intussusception is unusual. We suggest that an aggressive management approach using a combination of surgery and a newer technique like RFA can be attempted in patients with limited metastatic spread to liver to prolong the long-term survival in a subset of patients.     

Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases

Serum amyloid A protein (SAA) is an acute-phase reactant, known to mediate pro-inflammatory cellular responses. This study reports that CLA-1 (CD36 and LIMPII Analogous-1; human orthologue of the Scavenger Receptor Class B Type I (SR-BI)) mediates SAA uptake and downstream SAA signaling. Flow cytometry experiments revealed more than a 5-fold increase of Alexa-488 SAA uptake in HeLa cells stably transfected with CLA-1. Alexa 488-HDL uptake directly correlated with SAA uptake when determined in several CLA-1 stably transfected HeLa cell clones expressing various levels of CLA-1. SAA directly binds to CLA-1 as determined by cross-linking and colocalization of anti-CLA-1 antibody with SAA. SAA was co-internalized with transferrin to the endocytic recycling compartment pointing to a potential site of SAA metabolism. Alexa-488 SAA uptake in the CLA-1-overexpressing HeLa cells, as well as in THP-1 monocyte cell line, can be efficiently blocked by unlabeled SAA, high density lipoprotein, and other CLA-1 ligands. At the same time, markedly enhanced levels of phosphorylation of the mitogen-activated protein kinases (MAPKs), ERK1/2, and p38, were observed in cells stably transfected with CLA-1 cells following SAA stimulation when compared with mock transfected cells. The levels of the SAA-induced interleukin-8 (IL-8) secretion by CLA-1-overexpressing cells also significantly exceeded (5- to 10-fold) those detected for control cells. Synthetic amphipathic peptides possessing a structural alpha-helical motif inhibited SAA-induced activation of both MAPKs and IL-8 secretion in THP-1 cells. The results of this study demonstrate for the first time that CLA-1 functions as an endocytic SAA receptor and is involved in SAA-mediated cell signaling events associated with the immune-related and inflammatory effects of SAA.     

Class B scavenger receptor types I and II and CD36 targeting improves sepsis survival and acute outcomes in mice

Class B scavenger receptors (SR-Bs), such as SR-BI/II or CD36, bind lipoproteins but also mediate bacterial recognition and phagocytosis. In evaluating whether blocking receptors can prevent intracellular bacterial proliferation, phagocyte cytotoxicity, and proinflammatory signaling in bacterial infection/sepsis, we found that SR-BI/II- or CD36-deficient phagocytes are characterized by a reduced intracellular bacterial survival and a lower cytokine response and were protected from bacterial cytotoxicity in the presence of antibiotics. Mice deficient in either SR-BI/II or CD36 are protected from antibiotic-treated cecal ligation and puncture (CLP)-induced sepsis, with greatly increased peritoneal granulocytic phagocyte survival (8-fold), a drastic diminution in peritoneal bacteria counts, and a 50-70% reduction in systemic inflammation (serum levels of IL-6, TNF-α, and IL-10) and organ damage relative to CLP in wild-type mice. The survival rate of CD36-deficient mice after CLP was 58% compared with 17% in control mice. When compensated for mineralocorticoid and glucocorticoid deficiency, SR-BI/II-deficient mice had nearly a 50% survival rate versus 5% in mineralo-/glucocorticoid-treated controls. Targeting SR-B receptors with L-37pA, a peptide that functions as an antagonist of SR-BI/II and CD36 receptors, also increased peritoneal granulocyte counts, as well as reduced peritoneal bacteria and bacterium-induced cytokine secretion. In the CLP mouse sepsis model, L-37pA improved survival from 6 to 27%, reduced multiple organ damage, and improved kidney function. These results demonstrate that the reduction of both SR-BI/II- and CD36-dependent bacterial invasion and inflammatory response in the presence of antibiotic treatment results in granulocyte survival and local bacterial containment, as well as reduces systemic inflammation and organ damage and improves animal survival during severe infections.