Nanoparticles Targeted to Fibroblast Activation Protein Outperform PSMA for MRI Delineation of Primary Prostate Tumors

OnlinePublAccurate delineation of gross tumor volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumors, such as prostate cancer. Magnetic resonance imaging (MRI) of tumor targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-linear accelerator. Fibroblast activation protein (FAP) is overexpressed in stromal components of >90% of epithelial carcinomas. Herein, the authors compare targeted MRI of prostate specific membrane antigen (PSMA) with FAP in the delineation of orthotopic prostate tumors. Control, FAP, and PSMA-targeting iron oxide nanoparticles were prepared with modification of a lymphotropic MRI agent (FerroTrace, Ferronova). Mice with orthotopic LNCaP tumors underwent MRI 24 h after intravenous injection of nanoparticles. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles. FAP-targeted MRI increased the proportion of tumor contrast-enhancing black pixels by 13%, compared to PSMA. Analysis of changes in R2 values between healthy prostates and LNCaP tumors indicated an increase in contrast-enhancing pixels in the tumor border of 15% when targeting FAP, compared to PSMA. This study demonstrates the preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer.Nicole Dmochowska, Valentina Milanova, Ramesh Mukkamala, Kwok Keung Chow, Nguyen T. H. Pham, Madduri Srinivasarao, Lisa M. Ebert, Timothy Stait-Gardner, Hien Le, Anil Shetty, Melanie Nelson, Philip S. Low, and Benjamin Thierr

Enantioselective Dynamic Process Reduction of α- and β-Tetralone and Stereoinversion of Resulting Alcohols in a Selected Strain Culture

α-Tetralone and β-tetralone were subjected to biotransformation by 14 fungal strains. Enantiomeric purity of the products depended on the reaction time. 3-Day transformation of α-tetralone in Absidia cylindrospora culture gave S-(+)-1,2,3,4-tetrahydro-1-naftol of 92 % ee, whereas longer biotransformation time resulted in decrease of ee value. 3-Day transformation of β-tetralone by the same strain gave predominantly S-(−)-1,2,3,4-tetrahydro-2-naftol, whereas after 9 days of the reaction, the R-enantiomer with 85 % ee was isolated. Transformation of β-tetralone by Chaetomium sp. KCh 6651 gave pure (S)-(−)-1,2,3,4-tetrahydro-2-naftol in high yield at the concentration of 1 g/l. In this process, a non-selective carbonyl reduction was observed, followed by a selective oxidation of the R-alcohol

Yeast mitochondrial RNase P, RNase Z and the RNA degradosome are part of a stable supercomplex

Initial steps in the synthesis of functional tRNAs require 5′- and 3′-processing of precursor tRNAs (pre-tRNAs), which in yeast mitochondria are achieved by two endonucleases, RNase P and RNase Z. In this study, using a combination of detergent-free Blue Native Gel Electrophoresis, proteomics and in vitro testing of pre-tRNA maturation, we reveal the physical association of these plus other mitochondrial activities in a large, stable complex of 136 proteins. It contains a total of seven proteins involved in RNA processing including RNase P and RNase Z, five out of six subunits of the mitochondrial RNA degradosome, components of the fatty acid synthesis pathway, translation, metabolism and protein folding. At the RNA level, there are the small and large rRNA subunits and RNase P RNA. Surprisingly, this complex is absent in an oar1Δ deletion mutant of the type II fatty acid synthesis pathway, supporting a recently published functional link between pre-tRNA processing and the FAS II pathway—apparently by integration into a large complex as we demonstrate here. Finally, the question of mt-RNase P localization within mitochondria was investigated, by GFP-tracing of a known protein subunit (Rpm2p). We find that about equal fractions of RNase P are soluble versus membrane-attached

Transcriptome Analysis of the Arabidopsis Megaspore Mother Cell Uncovers the Importance of RNA Helicases for Plant Germline Development

Germ line specification is a crucial step in the life cycle of all organisms. For sexual plant reproduction, the megaspore mother cell (MMC) is of crucial importance: it marks the first cell of the plant “germline” lineage that gets committed to undergo meiosis. One of the meiotic products, the functional megaspore, subsequently gives rise to the haploid, multicellular female gametophyte that harbours the female gametes. The MMC is formed by selection and differentiation of a single somatic, sub-epidermal cell in the ovule. The transcriptional network underlying MMC specification and differentiation is largely unknown. We provide the first transcriptome analysis of an MMC using the model plant Arabidopsis thaliana with a combination of laser-assisted microdissection and microarray hybridizations. Statistical analyses identified an over-representation of translational regulation control pathways and a significant enrichment of DEAD/DEAH-box helicases in the MMC transcriptome, paralleling important features of the animal germline. Analysis of two independent T-DNA insertion lines suggests an important role of an enriched helicase, MNEME (MEM), in MMC differentiation and the restriction of the germline fate to only one cell per ovule primordium. In heterozygous mem mutants, additional enlarged MMC-like cells, which sometimes initiate female gametophyte development, were observed at higher frequencies than in the wild type. This closely resembles the phenotype of mutants affected in the small RNA and DNA-methylation pathways important for epigenetic regulation. Importantly, the mem phenotype shows features of apospory, as female gametophytes initiate from two non-sister cells in these mutants. Moreover, in mem gametophytic nuclei, both higher order chromatin structure and the distribution of LIKE HETEROCHROMATIN PROTEIN1 were affected, indicating epigenetic perturbations. In summary, the MMC transcriptome sets the stage for future functional characterization as illustrated by the identification of MEM, a novel gene involved in the restriction of germline fate

Peptidoglycan : structure, biological activity and chemical synthesis

The most important component of bacterial cell walls especially Gram-positive bacteria is peptidoglycan, called also murein, PGN. The first time this synonym was used in 1964 by Weidel and Pelzer [1]. Peptidoglycan is present in the outer layer of the cytoplasmic membrane and its structure. The structure of peptidoglycan depends on the bacteria strain. It is estimated that in Gram-negative bacteria, it occupies only about 10–20% of the total area of the cell wall, when in Gram-positive bacteria it is 50 and up to 90% of all space. Problems with isolation with high purity of biological material shows the need for developing techniques for chemical synthesis of peptidoglycan fragments and their analogs. In past few years there has been a growing interest within the synthesis of compounds glycoprotein (glycopeptides, peptidoglycan, etc.). As a basis for the construction of cell walls of many bacteria. Despite intensive research and gain significant knowledge of the physical and biological, chemical synthesis or biosynthesis (Fig. 5 and 6) of peptidoglycan, not so far failed to unambiguously determine its three-dimensional structure. The works of Kelman and Rogers [15] and Dimitriev [20] nearer picture of its structure. However, the time to develop in vivo visualization of cell structure it will be difficult to identify correctly peptidoglycan three-dimensional structure. Due to the important biological roles of murein, many research centers have taken to attempt their chemical synthesis. For biological research began to use chemically synthesized peptidoglycan fragments which guaranteed both uniform and a certain structure. An important roles in the development of methods of chemical synthesis of peptidoglycan had H. Chowdhury work, Fig. 8 [35], Hesek, Fig. 9 and 10 [36, 37], Dziarskiego [38] and Boneca [39] and Inamury [34, 40]

D-Ribono-1,4-lactone. Part 1, Preparation and seleced derivatives

Sugars are extremely important chiral substrates in organic synthesis. Thanks to the possibility of obtaining them from natural sources, their prices are relatively low which increases their attractiveness. d-Ribono-1,4-lactone is included in these compounds. For years it has enjoyed great interest as a substrate. In the early 1980’s two review articles were published in reputable journals [4, 5]. It has been a long time since these articles were published so we have decided to prepare a more up- -to-date review article in Polish. d-Ribono-1,4-lactone can be synthesized in many ways. The most interesting way seems to be the oxidation with KMnO4 [9] or molecular Br2 [10]. The use of bromine may appear to be harmful to the environment. That is why the search for more environmentally friendly methods is ongoing. However, the new methods are not as sufficiently satisfactory and often more expensive than the conventional, previously named methods. Therefore, the most commonly used method is the oxidation of D-ribose with molecular bromine. Very important derivatives of d-ribonolactone are acetal derivatives: 2,3-O-isopropylidene [10, 16] and 3,4-O-benzylidene derivatives [17]. They are often the starting materials for further synthesis. In the case of the latter compound the proper structure was determined by crystallography many years after its synthesis [18]. Very important group of derivatives are derivatives modificated at C-5: sulphonic [21], fluorine [22], chlorine [23], bromine [16, 24], azide [25] and phosphate [27]. Especially important are 5-bromo-5-deoxy derivatives. Examples of their use for the synthesis of thioalditols and thiosugars are described in the literature. It is also worth mentioning the possibility of synthesis of 1,2-unsaturated [28–30] and 2,3-unsaturated [31] derivatives. Presented examples of derivatives prove that using a d-ribono-1,4-lactone a whole range of derivatives extremely useful for further synthesis of more complex compounds can be obtained

Selected nucleoside antibiotics

Every year there has been a growing increase in infections caused by strains of bacteria resistant to multiple drugs. This prompts scientists to search for new antibiotics that would be able to fight these infections. New therapeutics used in medicine, which offer greater hopes are nucleoside antibiotics. They represent a large family of natural compounds exhibiting a variety of biological functions [1]. These include antifungal, antiviral, antibacterial, insecticides, immunosuppressants or anticancer properties. These broad-spectrum antibiotics can be divided into three main groups: • antibacterial nucleoside antibiotics, responsible for the inhibition of bacterial translocation of phospho-N-acetylpentapeptides, involved in the biosynthesis of peptidoglycan cell wall of bacteria; • antifungal nucleoside antibiotics, which role is to inhibit chitin synthase, or stopping construction of the cell wall of fungi; • antiviral antibiotics nucleoside, their mechanism of action is mainly based on blocking the biosynthesis of proteins by peptide inhibition transferase. In recent years much attention has been focused on the construction, mechanism of action and biosynthesis of antibiotics [1–3]. The development of genetic engineering has opened the way for combinatorial biosynthesis and obtaining new or hybrid compounds. In this work we would like to discuss some of bioactive naturally occurring nucleoside antibiotics, such as tunicamycin (Fig. 6) [19–22], mureidomycin (Fig. 8) [31–34], muramycin (Fig. 9) [36] or capuramycin (Fig. 10) [38]

D-Ribono-1,4-lactone. Part 2, Use in organic synthesis – selected reactions

There are many examples of syntheses with d-ribono-1,4-lactone as a substrate. Among all, its biggest advantage is undoubtedly its accessibility. It can be synthesized on a large scale from naturally available raw materials. Its characteristic feature is the stable configuration of individual carbon atoms in multiple reaction conditions. Very important is the presence of a carbonyl moiety, allowing for a variety of additions which is crucial for carbon-carbon bond formation, the most difficult synthesis in organic chemistry. In this article we present selected examples of articles that were published after 1984. In this year, the second article describing the Use of d-Ribonolactone in Organic Synthesis [36] was published. After this time many articles describing the use of the entitled lactone as a substrate in organic synthesis were published. We thought it would be worthwhile to present in Polish a selection of them. C-Glycosides and nucleoside analogs are a particularly important type of synthesized products. Examples of their synthesis are presented in this work, namely, neplanocin A [5], B [31] and F [24], citreovirdin [14], 2-bromopyridin α- and β-d-ribofuranosides [10], 4-deazaformicin A [27] and varitriol [ 33]