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The synthesis of the first conjugates of acridine with cobalt bis(dicarbollide) are reported. A novel 9-azido derivative of acridine was prepared through the reaction of 9-methoxyacridine with N3CH2CH2NH2, and its solid-state molecular structure was determined via single-crystal X-ray diffraction. The azidoacridine was used in a copper (I)-catalyzed azide-alkyne cycloaddition reaction with cobalt bis(dicarbollide)-based terminal alkynes to give the target 1,2,3-triazoles. DNA interaction studies via absorbance spectroscopy showed the weak binding of the obtained conjugates with DNA. The antiproliferative activity (IC50) of the boronated conjugates against a series of human cell lines was evaluated through an MTT assay. The results suggested that acridine derivatives of cobalt bis(dicarbollide) might serve as a novel scaffold for the future development of new agents for boron neutron capture therapy (BNCT). [ABSTRACT FROM AUTHOR]

A series of novel cobalt bis(dicarbollide)—curcumin conjugates were synthesized. Two conjugates were obtained through the nucleophilic ring-opening reaction of the 1,4-dioxane and tetrahydropyran derivatives of cobalt bis(dicarbollide) with the OH group of curcumin, and using two equiv. of the oxonium derivatives, two other conjugates containing two cobalt bis(dicarbollide) units per molecule were obtained. In contrast to curcumin, the conjugates obtained were found to be non-cytotoxic against both tumor and normal cell lines. The analysis of the intracellular accumulation of the conjugates by flow cytometry showed that all cobalt bis(dicarbollide)—curcumin conjugates entered HCT116 colorectal carcinoma cells in a time-dependent manner. New non-cytotoxic conjugates contain a large amount of boron atoms in the biomolecule and can potentially be used for further biological research into boron neutron capture therapy (BNCT). [ABSTRACT FROM AUTHOR]

A series of novel conjugates of cobalt bis(dicarbollide) and closo-dodecaborate with curcumin were synthesized by copper(I)-catalyzed azide-alkyne cycloaddition. These conjugates were tested for antibacterial activity. It was shown that all derivatives are active when exposed to Bacillus cereus ATCC 10702 and are not active against Gram-negative microorganisms and Candida albicans at the maximum studied concentration of 1000 mg/L. The conjugate of alkynyl-curcumin with azide synthesized from the tetrahydropyran derivative of cobalt bis(dicarbollide) exhibited activity against Gram-positive microorganisms: Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and the clinical isolate MRSA 17, that surpassed curcumin by 2–4 times. [ABSTRACT FROM AUTHOR]

Synthesis, NMR spectral data and crystal structure of 9,12-dibromo derivative of ortho-carborane are reported. [ABSTRACT FROM AUTHOR]

1-(3-Butyn-1-ylthio)-1,2-dicarba-closo-dodecaborane was synthesized by the alkylation of 1-mercapto-1,2-dicarba-closo-dodecaborane trimethylammonium salt with butyn-3-yl methanesulfonate. The deboronation reaction of this compound gave the corresponding derivative based on nido-carborane, namely, 7-(3-butyn-1-ylthio)-7,8-dicarba-undecaborate anion. 1,4-Disubstituted 1,2,3-triazoles based on closo- and nido-carboranes were synthesized by the CuI-catalyzed 1,3-dipolar [3+2] cycloaddition reaction of the acetylene derivatives of closo- and nido-carboranes with azidocholesterol. [ABSTRACT FROM AUTHOR]

[Display omitted] The novel conjugates of cholesterol with cobalt – bis(dicarbollide) were synthesized by the ring-opening reactions of the cyclic oxonium derivatives of [3,3′-Co(C 2 B 9 H 11) 2 ]– with the OH group of cholesterol 2-hydroxyethyl ether. The compounds obtained were tested for toxicity to glioblastoma U-87 MG cells and human embryo fibroblasts FECH-15 cells [ABSTRACT FROM AUTHOR]

Novel cobalt bis(dicarbollide) terminal alkynes with charge-compensated group were synthesized by the cleavage reactions of oxonium derivatives of cobalt bis(dicarbollide) with N,N-dimethylprop-2-yn-1-amine. The solid-state molecular structures of alkynes prepared from 1,4-dioxane and tetrahydropyran derivatives of cobalt and iron bis(dicarbollide) were determined by single-crystal X-ray diffraction. A series of zwitterionic conjugates of cobalt/iron bis(dicarbollide) with cholesterol were prepared using the copper(I)-catalyzed azide-alkyne cycloaddition reaction. [ABSTRACT FROM AUTHOR]

The nucleophilic ring-opening reaction of tetrahydropyran derivative of the closo-dode-caborate dianion with sodium azide in the presence of tetrabutylammonium bromide led to the novel azido-derivatives of[B12H12]2−. A Cu-catalyzed 1,3-dipolar [3+2] cycloaddition reaction of the closo-dodecaborate dianion azido-derivatives with alkynyl-cholesterol led to 1,4-disubstituted 1,2,3-triazoles with the closo-dodecaborate fragment at position 1. The resulting conjugates are potentially suitable for the development of liposomal drugs to selectively deliver boron into a tumor cell for boron neutron capture therapy of cancer. [ABSTRACT FROM AUTHOR]

Real-time monitoring is a key tool for several automated features in distribution system. However, due to the limited number of real-time measurements, distribution system monitoring generally relies on load modeling procedures. This paper presents field results for a real-time monitoring tool that was implemented on a Brazilian distribution utility to provide load values for service restoration software. The implemented tool comprises two steps. The first step consists of preprocessing routines that provide the required information for a real-time load estimator that is executed in the second step. The field results provide evidence of the practical viability of the implemented real-time monitoring tool, demonstrating the tool overcomes some usual limitations of real-time load estimation procedures. More specifically, the implemented tool is able to handle multiple and different types of real-time measurements, treat real-time measurements on the feeder and not only in the head of the feeder, handle obviously bad data, and to satisfy the performance requirements on practically sized distribution systems. Besides proposing and confirming a real-time monitoring tool on a real distribution system, this paper shares valuable utility experience on providing new insights and the challenges faced for real-time monitoring projects. [ABSTRACT FROM PUBLISHER]

New conjugates of cholesterol and cobalt bis(dicarbollide) were synthesized using 'click' cycloaddition of 3b-(2-azidoethyl) cholest-5-ene and acetylene-equipped cobalt bis(dicarbollides). The synthesized boronated cholesterols can be of interest for liposomal drug delivery for boron neutron capture therapy of cancer. [ABSTRACT FROM AUTHOR]

This work aims to characterize the water use of maize hybrid DKB 390 under suitable conditions of irrigation for both sufficient and below-optimal situations of nitrogen supply. Crop coefficient values for different stages are also presented as a result, in order to provide the basis for crop water budget and management throughout the cycle. A field experiment was carried out during the main season, in which biomass, soil moisture, leaf area, climate data and light transmittance were evaluated. These have allowed deriving water balance, use and efficiency. The mentioned genotype requires around 600 mm for high yield targets, being less efficient when led under below-optimal nitrogen fertilization. [ABSTRACT FROM AUTHOR]

The degradation of 15 organophosphorus insecticides was studied in drinking, ground, and surface waters under different laboratory-controlled and environmental conditions. Surface waters originated from rivers Savinja (near the city of Celje) and Kamniska Bistrica (at the spring), which both belong to the Danube river basin. Groundwater was collected from wells (70 m deep) in Ljubljana, which are the direct source of drinking water for the capital. These matrices were selected on the basis of their different chemical composition and microbial activity. Major factors influencing the degradation were determined, such as temperature, oxygen, sunlight, pH, and type of water. The degradation of atrazine, present in many water sources in Slovenija, was followed simultaneously as a reference under the same conditions. The degradation kinetics was followed by gas chromatography with mass-selective detection, which also allowed the identification of some degradation by-products, such as oxon analogues paraoxon, dyfoxon, malaoxon, phenyl-methyl sulfoxide, fenthion sulfone, phorate sulfoxide, and phorate sulfone. The results show that the half-lives of the selected organophosphorus insecticides varied from 4 to 192 days or more, depending on the water source and experimental conditions. As a result, kinetically constants and half-lives were calculated for every tested insecticide, and major degradation products were determined. [ABSTRACT FROM AUTHOR]

Little is known about the role of specific base modifications of transfer RNAs. Wyosine bases are tRNAPhe-specific modifications that are distinguished by differentiated, lateral side chains and base methylations appended to the core ring structure of a universally conserved G37, adjacent to the anticodon of Phe tRNAs. Based on previous data, we hypothesized that this modification was needed for -1 frameshifting. Using a reporter system incorporating a SCV-LA yeast virus slippery site for detecting -1 frameshifts in vivo, yeast strains were created that enabled chemical-genetic dissection of the role of different functional groups of wyebutosine that are added in a three-step post-transcriptional set of reactions. With this system, hypo-modification increased Phe-specific frameshifting, with incremental changes in frameshift efficiency after specific intermediates in the progression of wyebutosine synthesis. These data combined with investigations of wild-type and hypomodified tRNA binding to ribosomes suggest that frameshift efficiency is kinetically and not thermodynamically controlled. The progressive nature of frameshift efficiency with the stage of modification is consistent with a stepwise evolution and tuning of frame-shift potential. The stepwise tuning of frameshift efficiency could explain why tRNAPhe in some eukaryotes is not fully modified but, rather, hypomodifled to capture a specific frameshift potential. [ABSTRACT FROM AUTHOR]

Growth advantage in stationary phase (GASP) is the term used to describe the ability of mutants with an increased fitness from 10-day-old enterobacteria culture to outcompete 1-day-old cells of the same initial strain during a prolonged stationary phase, although the aged cells are introduced as a minority. We studied this bacterial trait in mixed cultures of two enterobacterial species, Escherichia coli and Salmonella enterica, wild type in addition to derived mutants from both strains that contain chromosomal-encoded resistance to either nalidixic acid or streptomycin. The strong GASP phenotype was obtained in mixed cultures with the aged mutant strains, but not when the isogenic antibiotic-sensitive strains were used. This phenomenon was associated with chromosomal rearrangements in 10-day-old bacterial antibiotic-resistant mutated cells. [ABSTRACT FROM AUTHOR]

Presents the findings of a study on the components neighboring 23S rRNA nucleotides A244 and U2604 within the peptidyl transferase center of Escherichia coli ribosomes. Photolysis of the 50S complex with photolabile oligonucleotide probes 1; Distortion of the peptidyl transferase center caused by 2'-O-methyloligoRNA binding.

9-HC≡CCH2Me2N-nido-7,8-C2B9H11, a previously described carboranyl terminal alkyne, was used for the copper(I)-catalyzed azide-alkyne cycloaddition with azido-3β-cholesterol to form a novel zwitter-ionic conjugate of nido-carborane with cholesterol, bearing a 1,2,3-triazol fragment. The conjugate of nido-carborane with cholesterol, containing a charge-compensated group in the linker, can be used as a precursor for the preparation of liposomes for BNCT (Boron Neutron Capture Therapy). The solid-state molecular structure of a nido-carborane derivative with the 9-Me2N(CH2)2Me2N-nido-7,8-C2B9H11 terminal dimethylamino group was determined by single-crystal X-ray diffraction. [ABSTRACT FROM AUTHOR]

The association between alcoholism and the Taql "A" and "B" polymorphic alleles at the DRD2 gene and 48-bp tandem repeat in exon 3 of dopamine D4 recepwr (DRD4) gene in 42 unrelated Slavic-surnamed patients and 76 normal controls was examined. The frequency of the A1 allele was higher in alcoholic patients and in alcoholic patients with a family history of alcoholism than in controls (Chi[sup 2] = 3.45, p < O. 001 and Chi[sup 2] = 3. 97, p < 0. 001, respectively). Moreover, the frequency of the A1 allele was higher in alcoholics with a family history of alcoholism than in alcoholics without a family history (Chi[sup 2] = 3.33, p < O. 001). The results of association analysis for both the Taql "B" and DRD4 alleles were negative for alcoholics in general, subgroups of alcoholics and normal controls. However, the 7-repeat allele (DRD4*7R) of DRD4 gene occurred at significantly higher frequency in alcoholics with a family history of alcoholism compared with those without a family history (Chi[sup 2] = 3.42, p < 0.01). The results indicate that the A1 allele of the DRD2 gene is associated with susceptibility to alcoholism in general The A1 allele, as well as the DRD4*7R allele, is significantly prevalent among alcoholics with a family history, in comparison with alcoholics without a family history, reflecting different roles of genetic factors in development of alcoholism. [ABSTRACT FROM AUTHOR]

Novel zwitter-ionic nido-carboranyl azide 9-N3(CH2)3Me2N-nido-7,8-C2B9H11 was prepared by the reaction of 9-Cl(CH2)3Me2N-nido-7,8-C2B9H11 with NaN3. The solid-state molecular structure of nido-carboranyl azide was determined by single-crystal X-ray diffraction. 9-N3(CH2)3Me2N-nido-7,8-C2B9H11 was used for the copper(I)-catalyzed azide-alkyne cycloaddition with phenylacetylene, alkynyl-3β-cholesterol and cobalt/iron bis(dicarbollide) terminal alkynes to form the target 1,2,3-triazoles. The nido-carborane-cholesterol conjugate 9-3β-Chol-O(CH2)C-CH-N3(CH2)3Me2N-nido-7,8-C2B9H11 with charge-compensated group in a linker can be used as a precursor for preparation of liposomes for Boron Neutron Capture Therapy (BNCT). A series of novel zwitter-ionic boron-enriched cluster compounds bearing a 1,2,3-triazol-metallacarborane-carborane conjugated system was synthesized. Prepared conjugates contain a large amount of boron atom in the biomolecule and potentially can be used for BNCT. [ABSTRACT FROM AUTHOR]

Antibody therapeutics are one of the most important classes of drugs. Antibody structures have become an integral part of predicting the behavior of potential therapeutics, either directly or as the basis of modeling. Structures of Fab:antigen complexes have even greater value. While the crystallization and structure determination of Fabs is easy relative to many other protein classes, especially membrane proteins, broad screening and optimization of crystalline hits is still necessary. Through a comprehensive review of rabbit Fab crystal contacts and their incompatibility with human Fabs, we identified a small secondary structural element from the rabbit light chain constant domain potentially responsible for hindering the crystallization of human Fabs. Upon replacing the human kappa constant domain FG loop (HQGLSSP) with the two residue shorter rabbit loop (QGTTS), we dramatically improved the crystallization of human Fabs and Fab:antigen complexes. Our design, which we call "Crystal Kappa", enables rapid crystallization of human fabs and fab complexes in a broad range of conditions, with less material in smaller screens or from dilute solutions. [ABSTRACT FROM AUTHOR]

Reactions of [8-HCCCH 2 O-8′-I-3,3′-Co(1,2-C 2 B 9 H 10 ) 2 ] - ([ 2 ] Cs ) with 5-iodo-2’-deoxyuridine under Sonogashira reaction conditions resulted in a cobalt bis(1,2-dicarbollide)(-I) 5-ethynyl-2'-deoxyuridine conjugate ([ 3 ] Cs ) linked via short spacer. Its intramolecular cyclization led to furo [2,3-d]pyrimidin-2(3H)-one isomer ([ 4 ] Cs ). Compounds [3]Cs and [4]Cs demonstrated moderate cytotoxicity, however they did not have antiviral activity against the viruses tested. A new terminal charge-compensated cobalt bis(1,2-dicarbollide)(-I) derivative with terminal alkyne group ( 5 ) was synthesized from 8,8’-μ-I-3,3′-Co(1,2-C 2 B 9 H 10 ) 2 and dimethylpropargyl amine. It was found that contrary to [2]Cs compound 5 did not react with 5-iodo-2’-deoxyuridine under Sonogashira reaction conditions. Total electrostatic potential (TEP) calculations gave explanation of this phenomenon. [ABSTRACT FROM AUTHOR]

Boron-containing conjugates of cholesterol were synthesized by the copper(i)-catalyzed 1,3-dipolar [3+2] cycloaddition reactions of cobalt and iron bis(dicarbollide) azide derivatives with alkynyl cholesterol. The antiproliferative activity (IC50) of the conjugates was evaluated against a series of human cell lines by the MTT assay. All conjugates were shown to be nontoxic (IC50 >200 µmol L−1) and to be applicable for the preparation of boron-containing liposomes as potential drugs for boron-neutron capture therapy (BNCT) of cancer. [ABSTRACT FROM AUTHOR]

Novel fluorescent 7-methoxy- and 7-(diethylamino)-coumarins modified with azido-group on the side chain have been synthesized. Their photophysical properties and single crystals structure characteristics have been studied. In order to demonstrate the possibilities of fluorescent labeling, obtained coumarins have been tested with closo-dodecaborate derivative bearing terminal alkynyl group. CuI catalyzed Huisgen 1,3-dipolar cycloaddition reaction has led to fluorescent conjugates formation. The absorption–emission spectra of the formed conjugates have been presented. The antiproliferative activity and uptake of compounds against several human cell lines were evaluated. [ABSTRACT FROM AUTHOR]

High anxiety and poor emotion regulation have been found to function as independent causes of stress to the autonomic nervous system. The aim of this study was to further explore how these factors may interact to control heart rate variability. Fifty college students took part in a three-part cardiac recording session followed by questionnaires on trait worry and emotion regulation. An interaction for trait worry and emotion reappraisal was found on two markers of heart rate variability. Low trait worriers with high emotion reappraisal had higher vagal tone than the other three groups. This finding was across all three phases with no specific reactivity or recovery difference. Emotion suppression was not found to significantly impact vagal tone. The negative impacts of trait worry and emotion regulation on heart rate variability were found in this sample of healthy college-aged individuals. Specifically, high trait worry could have a deleterious effect on parasympathetic control of the heart. Emotion regulation skills meanwhile can function as a buffer to stress and a reliance on sympathetic control. [ABSTRACT FROM AUTHOR]

Abstract: Aminoacyl transfer RNA (tRNA) synthetases are intensely studied enzymes because of their importance in the establishment of the genetic code and their connection to disease and medicine. During the advancement of this field, several assays were developed. Despite many innovations, the sensitivity, simplicity, and reliability of the radiometric assays (which were among the first to be developed) have ensured their continued use. Four activities are measured by these assays: active site titration, amino acid activation, aminoacylation, and posttransfer editing (deacylation). In an effort to maintain the advantage of these assays while enhancing throughput, reducing waste, and improving data quality, a universal 96-well filter plate format was developed. This format facilitates the assays for all four of the widely studied activities. [Copyright &y& Elsevier]

A series of water-soluble conjugates of 7-diethylamino-4-hydroxycoumarin with four different anionic polyhedral boron clusters was synthesized. The distribution coefficients (log D 7.4) as a measure of the ability to pass through the cell membrane for novel compounds were determined via a shake-flask methodology in n-octanol/aqueous (pH 7.4) buffer solution system. For two closo -dodecaborate modifications log D 7.4 displayed negative lipophilicity values. Conjugates of metallacarboranes containing Co and Fe as long as two 7,8-dicarba- nido -undecaborate coumarin anions were found to have appropriate lipophilicity for medicinal applications. • Novel anionic coumarin conjugates with several boron clusters were synthesized. • The first iron bis(1,2-dicarbollide) conjugate with coumarin is described. • Distribution coefficients (log D7.4) of prepared compounds were determined. • Some conjugates were found to have appropriate lipophilicity for medicinal use. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) remains an important treatment arm for cancer patients with locally invasive malignant tumors. This therapy needs a significant amount of boron to deposit in cancer tissues selectively, sparing other healthy organs. Most of the liposomes contain water-soluble polyhedral boron salts stay in the core of the liposomes and have low encapsulation efficiency. Thus, modifying the polyhedral boron core to make it hydrophobic and incorporating those into the lipid layer could be one of the ways to increase drug loading and encapsulation efficiency. Additionally, a systematic study about the linker-dependent effect on drug encapsulation and drug-release is lacking, particularly for the liposomal formulation of hydrophobic-drugs. To achieve these goals, liposomal formulations of a series of lipid functionalized cobalt bis(dicarbollide) compounds have been prepared, with the linkers of different hydrophobicity. Hydrophobicity of the linkers have been evaluated through logP calculation and its effect on drug encapsulation and release have been investigated. The liposomes have shown high drug loading, excellent encapsulation efficiency, stability, and non-toxic behavior. Release experiment showed minimal release of drug from liposomes in phosphate buffer, ensuring some amount of drug, associated with liposomes, can be available to tumor tissues for Boron Neutron Capture Therapy. [ABSTRACT FROM AUTHOR]

Novel nido -carboranyl azide [7-N 3 CH 2 CH 2 OCH 2 CH 2 O-7,8-C 2 B 9 H 11 - was prepared by the reaction of 1-hydroxy- ortho -carborane with bis(2-chloroethyl) ether followed by the conversion to its nido -form and reactions with sodium iodide and sodium azide. Previously undescribed carboranyl azides 1-N 3 CH 2 CH 2 OCH 2 CH 2 S-1,2-C 2 B 10 H 11 and [7-N 3 CH 2 CH 2 OCH 2 CH 2 S-7,8-C 2 B 9 H 11 - were synthesized by alkylation of trimethylammonium salt of 1-mercapto- ortho -carborane with bis(2-chloroethyl) ether followed by reactions with sodium iodide and with sodium azide and by the conversion of closo -derivative to water soluble nido -form. closo - and nido -Carboranyl azides 1-N 3 CH 2 CH 2 OCH 2 CH 2 S-1,2-C 2 B 10 H 11 and [7-N 3 CH 2 CH 2 OCH 2 CH 2 S-7,8-C 2 B 9 H 11 - were used for the copper(I)-catalyzed azide-alkyne cycloaddition with phenyacetylene. The compounds prepared can be used for the copper(I)-catalyzed сonjugation with biomolecules that act as tumor-targeting vectors for radionuclide diagnostics and boron neutron capture therapy of cancer. Image 1 • Novel carboranyl azides with diethylene glycol-like flexible spacer were synthesized. [ABSTRACT FROM AUTHOR]

Charge-compensated mono- and bidentate nido-carboranyl thioether ligands [7-MeS-9-Me3N-7,8-C2B9H10], [7-MeS-11-Me3N-7,8-C2B9H10] and [7,8-(MeS)2-9-Me3N-7,8-C2B9H9] were synthesized. They readily react with labile tungsten carbonyl complex W(CO)5(THF) to give the corresponding σ-complexes (CO)5W[7-MeS-9-Me3N-7,8-C2B9H10-κ1-S(7)], (CO)5W[7-MeS-11-Me3N-7,8-C2B9H10-κ1-S(7)] and (CO)5W[nido-7,8-(MeS)2-9-Me3N-7,8-C2B9H9-κ1-S(7)], respectively. The reaction of [7,8-(MeS)2-9-Me3N-7,8-C2B9H9] with W(CO)3(MeCN)3 produced chelate complex (CO)4W[7,8-(MeS)2-9-Me3S-7,8-C2B9H9-κ2-S(7),S(8)]. The synthesized metallocomplexes were characterized by NMR spectroscopy and single crystal X-ray diffraction. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular diseases (CVD) are the main cause of death worldwide, and according to experts, they will continue to dominate the structure of global mortality. Aim: The effectiveness of the multimodal low-opioid anesthesia technique in performing coronary artery bypass graft operations with artificial blood circulation. Material and methods: Ninety-six patients aged 61.8 ±10.4 years underwent coronary artery bypass grafting under artifi- cial blood circulation. Group I: propofol, sevoflurane, fentanyl, pipecuronium bromide (standard doses). Group II: dexketoprofen trometamol (50 mg), intravenous lidocaine (1% - 1 mg/kg bolus) and continuous lidocaine infusion (1.5-2 mg/kg/h), propofol, ketamine (0.5 mg/kg), magnesia sulfate, minimal doses of fentanyl. Results: Average duration of anesthesia -- 257.4 ±19.1 min; assisted blood circulation -- 55 ±10 min. Mean dose of fentanyl in group I -- 4.66 ±1.58 µg/kg/h, in group II -- 1.29 ±0.32 µg/kg/h. Standard lab values and stress hormonal changes were within the normal range (mean cortisol: 479.3 ±26.4 nmol/l, lactate 1.61 ±0.2 mmol/l, glucose 6.42 ±0.9 mmol/l). Changes in heart rate within group I had a significant amplitude of dynamics, while in group II, these values were relatively at the same level throughout the entire anesthetic provision. Mean arterial pressure changes in group I were characterized by a significant reduction at the stage of induction, support and sternum reduction, whereas in group II it was relatively at the same level during the entire anesthetic management and significantly differed from baseline only at the stage of induction. Conclusions: Multimodal low-opioid anesthesia during coronary artery bypass surgery with artificial blood circulation allows one to ensure adequate analgesia and avoid the intraoperative usage of routine doses of fentanyl, as indicated by the absence of hemodynamic and endocrine-metabolic changes. [ABSTRACT FROM AUTHOR]

8-Tetrahydrofuronium and 8-tetrahydropyronium derivatives of iron bis(dicarbollide)(-I) were synthesized. Their reactions of ring cleavage by MeOH, N3−, amines and 1,2-bis(diphenylphosphino)ethane were investigated. 8-Tetrahydrofuronium iron bis(dicarbollide)(-I) was found to be more active in these reactions in comparison with 8-tetrahydropyronium and 8-dioxonium species, respectively. The first conjugates of iron bis(1,2-dicarbollide)(-I) with 2′-deoxyadenosine modified via the C-8 position of the purine base were synthesized. Reactions of these oxonium compounds with 1,2-bis(diphenylphosphino)ethane (dppe) led to zwitter-ionic monophosphonium salts. One of these compounds has given rise to a novel ferracarborane/cobaltacarborane hybrid complex. [ABSTRACT FROM AUTHOR]

The enhancer-of-zeste homolog 2 (EZH2) gene product is an 87 kDa polycomb group (PcG) protein containing a C-terminal methyltransferase SET domain. EZH2, along with binding partners, i.e., EED and SUZ12, upon which it is dependent for activity forms the core of the polycomb repressive complex 2 (PRC2). PRC2 regulates gene silencing by catalyzing the methylation of histone H3 at lysine 27. Both overexpression and mutation of EZH2 are associated with the incidence and aggressiveness of various cancers. The novel crystal structure of the SET domain was determined in order to understand disease-associated EZH2 mutations and derive an explanation for its inactivity independent of complex formation. The 2.00 Å crystal structure reveals that, in its uncomplexed form, the EZH2 C-terminus folds back into the active site blocking engagement with substrate. Furthermore, the S-adenosyl-L-methionine (SAM) binding pocket observed in the crystal structure of homologous SET domains is notably absent. This suggests that a conformational change in the EZH2 SET domain, dependent upon complex formation, must take place for cofactor and substrate binding activities to be recapitulated. In addition, the data provide a structural context for clinically significant mutations found in the EZH2 SET domain. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferases (PRMTs) play important roles in several cellular processes, including signaling, gene regulation, and transport of proteins and nucleic acids, to impact growth, differentiation, proliferation, and development. PRMT5 symmetrically dimethylates the two-terminal (ω-guanidino nitrogens of arginine residues on substrate proteins. PRMT5 acts as part of a multimeric complex in concert with a variety of partner proteins that regulate its function and specificity. A core component of these complexes is the WD40 protein MEP50/WDR77/p44, which mediates interactions with binding partners and substrates. We have determined the crystal structure of human PRMT5 in complex with MEP50 (methylosome protein 50), bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed (β-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most malignant tumors with poor prognosis and outcomes. Although smaller particle size can lead to higher blood-brain barrier (BBB)-permeability of the nanomaterials, most of the reported BBB-crossable nanomaterials for targeted GBM therapy are larger than 24 nm. To realize theranostics of GBM, co-loading of therapeutic and diagnostic agents on the same nanomaterials further results in larger particle size. In this study, we developed a kind of novel BBB-transportable nanomaterials smaller than 14 nm for high-efficiency theranostics of GBM (i.e. , high contrast magnetic resonance imaging (MRI) and radiosensitization of GBM). Typically, poly(acrylic acid) (PAA) stabilized extremely small gadolinium oxide nanoparticles with modification of reductive bovine serum albumin (ES-GON-rBSA) was synthesized in water phase, resulting in excellent water-dispersibility. RGD dimer (RGD2, Glu-{Cyclo[Arg-Gly-Asp-(D-Phe)-Lys]} 2) and lactoferrin (LF) were then conjugated to the ES-GON-rBSA to obtain composite nanoparticle ES-GON-rBSA-LF-RGD2 with extraordinary relaxivities (r 1 = 60.8 mM−1 s−1, r 2 / r 1 = 1.1). The maximum signal enhancement (ΔSNR) for T 1 -weighted MRI of tumors reached up to 423 ± 42% at 12 h post-injection of ES-GON-rBSA-LF-RGD2, which is much higher than commercial Gd-chelates (<80%). ES-GON-rBSA-LF-RGD2 exhibited high biocompatibility and can transport across the in vitro BBB model and the in vivo BBB of mice due to its small particle size (d h = 13.4 nm) and LF receptor mediated transcytosis. Orthotopic GBM studies reinforce that ES-GON-rBSA3-LF-RGD2 can accumulate in the orthotopic GBM and enhance the radiation therapy of GBM as an effective radiosensitizing agent. [ABSTRACT FROM AUTHOR]