Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism

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High and ultra‐high definition of infrared spectral histopathology gives an insight into chemical environment of lung metastases in breast cancer

Using high definition (HD) and ultra‐high definition (UHD) of Fourier‐transform infrared (FTIR) spectroscopic imaging, we characterized spectrally pulmonary metastases in a murine model of breast cancer comparing them with histopathological results (Hematoxylin and eosin [H&E] staining). This comparison showed excellent agreement between the methods in case of localization of metastases with size below 1 mm and revealed that label‐free HD and UHD IR spectral histopathology distinguish the type of neoplastic cells. We primary focused on differentiation between metastatic foci in the pleural cavity from cancer cells present in lung parenchyma and inflamed cells present in extracellular matrix of lungs due to growing of advanced metastases. In addition, a combination of unsupervised clustering and IR imaging indicated the high sensitivity of FTIR spectroscopy to identify chemical features of small macrometastases located under the pleural cavity and during epithelial‐mesenchymal transition. FTIR‐based spectral histopathology was proved to detect not only phases of breast cancer metastasis to lungs but also to differentiate various origins of metastases seeded from breast cancer.      

Challenging a Paradigm: the Role of DNA Homology in Tyrosine Recombinase Reactions

Summary: A classical feature of the tyrosine recombinase family of proteins catalyzing site-specific recombination, as exemplified by the phage lambda integrase and the Cre and Flp recombinases, is the ability to recombine substrates sharing very limited DNA sequence identity. Decades of research have established the importance of this short stretch of identity within the core regions of the substrates. Since then, several new enzymes that challenge this paradigm have been discovered and require the role of sequence identity in site-specific recombination to be reconsidered. The integrases of the conjugative transposons such as Tn916, Tn1545, and CTnDOT recombine substrates with heterologous core sequences. The integrase of the mobilizable transposon NBU1 performs recombination more efficiently with certain core mismatches. The integration of CTX phage and capture of gene cassettes by integrons also occur by altered mechanisms. In these systems, recombination occurs between mismatched sequences by a single strand exchange. In this review, we discuss literature that led to the formulation of the current strand-swapping isomerization model for tyrosine recombinases. The review then focuses on recent developments on the recombinases that challenged the paradigm that was derived from the studies of early systems.     

The phosphoramidate ProTide approach greatly enhances the activity of β-2′-C-methylguanosine against hepatitis C virus

β-2′-C-Methyl purines (1, 2) are known inhibitors of hepatitis C virus (HCV). We herein report the synthesis, biological and enzymatic evaluation of their 5′-phosphoramidate ProTides. Described herein are seven l-alanine phosphoramidate derivatives with variations to the amino acid ester. The 1-naphthyl phosphoramidate of β-2′-methylguanosine containing the benzyl ester (20) was the most active at 0.12 μM, an 84-fold of increase in activity compared to the parent nucleoside (2) with no increase of cytotoxicity. The carboxypeptidase mediated hydrolysis of several ProTides showed a predictive correlation with their activity versus HCV in replicon.     

Synthesis and NMR properties of novel 5,6-dihydroborauracil derivatives

Novel boron compounds - 5,6-saturated borauracil derivatives (4-bromo-5,6-dihydroborauracil, 4-hydroxy-5,6-dihydroborauracil and 4-methoxy-5,6-dihydroborauracil) are presented along with other boron compounds obtained from N-vinylurea: N-substituted β-boronic amino acid - 2-{[(dihydroxyborano-amino)(dihydroxyboranooxy)methyl]-amino}ethylboronic acid and substituted methoxy-borane O-[(1-amino-1-N-vinylamino)methyl]dihydroxyboronate.     

Synthesis and NMR properties of derivatives of 5,6-dihydroborauracil and 5,6-dihydroborathymine

Novel boron compounds, a series of 4-hydroxy-5,6-dihydroborauracil and 4-hydroxy-5,6-dihydroborathymine derivatives containing various substituents at 3-, 5- and 6-positions, is presented. The spectroscopic properties, along with analyses of NMR-controlled boron compound–alcohol and boron compound–amine interactions, proves the existence of sp³-hybridized, stable B,B-bis-methoxy-5,6-dihydroborauracils and pyridine-/n-butylamine-5,6-dihydroborauracils ate-complexes in solution.     

Comparative molecular cytogenetic analysis of three <Emphasis Type="Italic">Leuciscus</Emphasis> species (Pisces,Cyprinidae) using chromosome banding and FISH with rDNA

A comparative molecular cytogenetic analysis was performed on three species of the genus Leuciscus viz. ide L. idus, chub L. cephalus and dace L. leuciscus distributed in Poland, using C-, Ag- and chromomycin A₃ (CMA₃)-stainings and fluorescence in situ hybridization (FISH) with 5.8S + 28S rDNA as a probe. Although the three species examined shared 2n = 50 chromosomes and the largest acrocentric chromosome pair in the complement, they were characterized with karyotypic differences in terms of the number of uni- and biarmed chromosomes and the localization of nucleolar organizer regions (NORs) revealed by Ag-staining and FISH. L. idus and L. cephalus showed the rDNA sites on the long arms of one submetacentric (SM) chromosome pair and on the short arms of one subtelocentric (ST) chromosome pair, respectively. These NORs were CMA₃-positive, GC-rich and C-positive heterochromatic sites in both species. Such chromosome banding features were also true for four NORs localizing on one of each SM and ST pair in L. leuciscus, but considerable numerical NOR polymorphism became apparent with Ag-staining and FISH due to a different combination of these NOR-bearing SMs and STs in this dace. The present results indicate that the molecular cytogenetic analysis applied herein may become useful to elucidate the karyotype evolution and phylogenetic relationships among the species in the genus Leuciscus and other related groups.     

Quantification of Normal Cell Fraction and Copy Number Neutral LOH in Clinical Lung Cancer Samples Using SNP Array Data

Background

Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Since tumor tissue invariably contains genetically normal stromal cells, this may lead to a failure to detect aberrations in the tumor cells.

Principal Finding

Using SNP array data from 44 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells in combination with SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection.

Conclusion

Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes.     

Potassium channels in the mitochondria of unicellular eukaryotes and plants

The functional characterisation of potassium channels found in the mitochondria of plants and unicellular eukaryotes is critically discussed herein, with a focus on the ATP-sensitive potassium channel and the large-conductance Ca²⁺-activated potassium channel (mitoBK_Ca channel). The physiological functions of these channels are not completely understood. We discuss the functional connections and roles of potassium channels, uncoupling protein and alternative oxidase, three energy-dissipating systems that exist in the mitochondrial respiratory chain of plants and some unicellular eukaryotes, which include preventing the production of reactive oxygen species.     

Use of the chromosomal co-location of the minor 5S and the major 28S rDNA as a cytogenetic marker within the genus Leuciscus (Pisces, Cyprinidae)

The chromosomes of three species from the genus Leuciscus (the ide L. idus, the European chub L. cephalus and the common dace L. leuciscus) were examined with the FISH technique for 5S and 28S rDNA probes. The analysis showed that among the three examined species, 5S rDNA signals were located on two large and four small subtelocentric chromosomes in L. leuciscus, on one large and five small subtelocentric chromosomes in L. idus, while in L. cephalus the probe signals were found on two metacentric chromosomes and one large and one small subtelocentric chromosome pairs. In all analysed species, the 28S rDNA probe signals were placed on only one chromosome pair, subtelocentric in the common dace and the European chub, and submetacentric in the ide. The three species differed in the number of sites in which both probe signals were present. In conclusion, the co-location of the 5S and 28S rDNA proved to be a useful cytogenetic marker among the studied fishes. Moreover, this marker could be adapted to other cyprinids.