Doxorubicin-induced ovarian toxicity

Background  

Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries.     

Intracellular cysteine residues in the tail of MHC class I proteins are crucial for extracellular recognition by leukocyte Ig-like receptor 1

The activity of NK cells is regulated by activating receptors that recognize mainly stress-induced ligands and by inhibitory receptors that recognize mostly MHC class I proteins on target cells. Comparing the cytoplasmic tail sequences of various MHC class I proteins revealed the presence of unique cysteine residues in some of the MHC class I molecules which are absent in others. To study the role of these unique cysteines, we performed site specific mutagenesis, generating MHC class I molecules lacking these cysteines, and demonstrated that their expression on the cell surface was impaired. Surprisingly, we demonstrated that these cysteines are crucial for the surface binding of the leukocyte Ig-like receptor 1 inhibitory receptor to the MHC class I proteins, but not for the binding of the KIR2DL1 inhibitory receptor. In addition, we demonstrated that the cysteine residues in the cytoplasmic tail of MHC class I proteins are crucial for their egress from the endoplasmic reticulum and for their palmitoylation, thus probably affecting their expression on the cell surface. Finally, we show that the cysteine residues are important for proper extracellular conformation. Thus, although the interaction between leukocyte Ig-like receptor 1 and MHC class I proteins is formed between two extracellular surfaces, the intracellular components of MHC class I proteins play a crucial role in this recognition.     

A probabilistic methodology for integrating knowledge and experiments on biological networks.

Biological systems are traditionally studied by focusing on a specific subsystem, building an intuitive model for it, and refining the model using results from carefully designed experiments. Modern experimental techniques provide massive data on the global behavior of biological systems, and systematically using these large datasets for refining existing knowledge is a major challenge. Here we introduce an extended computational framework that combines formalization of existing qualitative models, probabilistic modeling, and integration of high-throughput experimental data. Using our methods, it is possible to interpret genomewide measurements in the context of prior knowledge on the system, to assign statistical meaning to the accuracy of such knowledge, and to learn refined models with improved fit to the experiments. Our model is represented as a probabilistic factor graph, and the framework accommodates partial measurements of diverse biological elements. We study the performance of several probabilistic inference algorithms and show that hidden model variables can be reliably inferred even in the presence of feedback loops and complex logic. We show how to refine prior knowledge on combinatorial regulatory relations using hypothesis testing and derive p-values for learned model features. We test our methodology and algorithms on a simulated model and on two real yeast models. In particular, we use our method to explore uncharacterized relations among regulators in the yeast response to hyper-osmotic shock and in the yeast lysine biosynthesis system. Our integrative approach to the analysis of biological regulation is demonstrated to synergistically combine qualitative and quantitative evidence into concrete biological predictions.     

E-cadherin in oral SCC: an analysis of the confusing literature and new insights related to its immunohistochemical expression

E-cadherin plays a crucial structural role in cell-cell contacts in epithelial tissues, and a functional role in signaling pathways that regulate cell proliferation, differentiation, and survival. Reduced immunoexpression of E-cadherin adhesions is largely considered as being equivalent to defective functionality and malignancy, and has been used as a prognostic parameter. A critical analysis of studies on E-cadherin immunoexpression in oral carcinomas revealed a wide range of both technical and interpretational aspects. This paper highlights biological characteristics of E-cadherin with respect to its expression in normal and neoplastic epithelial cells and to its interrelations with the tumor microenvironment that can have an impact on immunohistochemical results and their application in the clinical setting.     

Impact of short-term acidification on nitrification and nitrifying bacterial community dynamics in soilless cultivation media

Soilless medium-based horticulture systems are highly prevalent due to their capacity to optimize growth of high-cash crops. However, these systems are highly dynamic and more sensitive to physiochemical and pH perturbations than traditional soil-based systems, especially during nitrification associated with ammonia-based fertilization. The objective of this study was to assess the impact of nitrification-generated acidification on ammonia oxidation rates and nitrifying bacterial community dynamics in soilless growth media. To achieve this goal, perlite soilless growth medium from a commercial bell pepper greenhouse was incubated with ammonium in bench-scale microcosm experiments. Initial quantitative real-time PCR analysis indicated that betaproteobacterial ammonia oxidizers were significantly more abundant than ammonia-oxidizing archaea, and therefore, research focused on this group. Ammonia oxidation rates were highest between 0 and 9 days, when pH values dropped from 7.4 to 4.9. Pyrosequencing of betaproteobacterial ammonia-oxidizing amoA gene fragments indicated that r-strategist-like Nitrosomonas was the dominant ammonia-oxidizing bacterial genus during this period, seemingly due to the high ammonium concentration and optimal growth conditions in the soilless media. Reduction of pH to levels below 4.8 resulted in a significant decrease in both ammonia oxidation rates and the diversity of ammonia-oxidizing bacteria, with increased relative abundance of the r-strategist-like Nitrosospira. Nitrite oxidizers (Nitrospira and Nitrobacter) were on the whole more abundant and less sensitive to acidification than ammonia oxidizers. This study demonstrates that nitrification and nitrifying bacterial community dynamics in high-N-load intensive soilless growth media may be significantly different from those in in-terra agricultural systems.