bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the antioxidant activity of phenols and tannic acid determination with Mn3O4nano-octahedrons as an oxidase mimic
Authors: Zhang Xiaodan , Huang Yuming
Published: August 2015

Mn3O4nano-octahedrons as an effective oxidase mimic for the preliminary assessment of phenols' antioxidant activity and visual determination of tannic acid were demonstrated.
Optimization of the preconcentration of seleniumivon palladium nanoparticles (PdNPs), using multivariate analysis for the inorganic speciation of selenium in environmental water samples
Authors: Kumar G. Kiran , Sharma P. S. , Sounderajan Suvarna , Datta D. , Singhal R. K. , Udas A. C.
Published: August 2015

A simple method for the characterization and quantification of ultratrace quantities of Se(iv) in environmental water samples by preconcentration of selenium(iv) on PdNPs was optimized by employing the multivariate strategy.
Rhodium-catalysed alkoxylation/acetalization of diazo compounds: one-step synthesis of highly functionalised quaternary carbon centres
Authors: Pospech Jola , Lennox Alastair J. J. , Beller Matthias
Published: August 2015

An intermolecular tandem reaction for the rapid build-up of densely functionalised α-alkoxy-β-oxo-esters has been developed.
Synthesis of a diboryl-N-heterocycle and its conversion to a bidentate cationic Lewis acid
Authors: Farrell Jeffrey M. , Stephan Douglas W.
Published: August 2015

Sequential reaction of 2-lithio-1-methylimidazole with 9-borabicyclo[3.3.1]nonane (9-BBN) dimer and 9-Cl-9-BBN yields diboryl-N-heterocycle C4H5N2(H)(BC8H14)2 (1).
Hydroxyl radical generation by cactus-like copper oxide nanoporous carbon catalysts for microcystin-LR environmental remediation
Authors: Karthikeyan S. , Dionysiou Dionysios D. , Lee Adam F. , Suvitha S. , Maharaja P. , Wilson Karen , Sekaran G.
Published: August 2015

Copper oxide supported on nanoporous activated carbon (CuO-NPAC) is reported for the aqueous phase catalytic degradation of cyanotoxin microcystin-LR (MC-LR).
Improved benzene production from methane dehydroaromatization over Mo/HZSM-5 catalysts via hydrogen-permselective palladium membrane reactors
Authors: Natesakhawat S. , Means N. C. , Howard B. H. , Smith M. , Abdelsayed V. , Baltrus J. P. , Cheng Y. , Lekse J. W. , Link D. , Morreale B. D.
Published: August 2015

Catalytic Pd membrane reactors improve C6H6yield compared to fixed-bed reactors.
Piperazine linked salicylaldoxime and salicylaldimine-based dicopper(ii) receptors for anions
Authors: De Silva D. Nirosha T. , Jameson Geoffrey B. , Pannu Ajay Pal Singh , Pouhet Raphëlle , Wenzel Marco , Plieger Paul G.
Published: August 2015

A series of piperazine dicopper metallo-macrocyles have been synthesised and the crystal structures reveal the extent that intramolecular hydrogen binding influences the resulting structure and ability to encapsulated anions.
Morus nigra leaf extract improves glycemic response and redox profile in the liver of diabetic rats
Authors: Araujo Carolina Morais , Lúcio Karine de Pádua , Silva Marcelo Eustáquio , Isoldi Mauro César , de Souza Gustavo Henrique Bianco , Brandão Geraldo Célio , Schulz Richard , Costa Daniela Caldeira
Published: August 2015

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia and increased oxidative stress. The treatment withMorus nigracan improve oxidative stress and complications due to diabetes.
Nutritional and health-promoting properties of bean paste fortified with onion skin in the light of phenolic–food matrix interactions
Authors: Sęczyk Ł. , Świeca M. , Gawlik-Dziki U.
Published: August 2015

The study examined the effect of fortification of bean paste with onion skin phenolics.
Inhibition of phosphatidylinositol-3,4,5-trisphosphate binding to the AKT pleckstrin homology domain by 4-amino-1,2,5-oxadiazole derivatives
Authors: Gorai Sukhamoy , Paul Saurav , Sankaran Ganga , Borah Rituparna , Santra Manas Kumar , Manna Debasis
Published: August 2015

4-Amino-1,2,5-oxadiazole derivatives has been developed as an inhibitor of AKT pleckstrin homology domain.
Synthesis of N-dialkylphosphoryl iminosugar derivatives and their immunosuppressive activities
Authors: Yang Xuemei , Xiong De-Cai , Song Chengcheng , Tai Guihua , Ye Xin-Shan
Published: August 2015

Twelve novel N-dialkylphosphoryliminosugar derivatives were synthesized and their immunosuppressive activities were evaluated on the proliferation of the mouse splenocytes and the secretion of IFN-γ and IL-4.
One-pot synthesis of hyperstar polymers via sequential ATRP of inimers and functional monomers in aqueous dispersed media
Authors: Wang Xiaofeng , Graff Robert W. , Shi Yi , Gao Haifeng
Published: August 2015

A one-pot synthesis was reported to produce hyperstar polymers with high molecular weight, low polydispersity and no detectable star coupling reactions.
Fabrication of polypyrrole nanoplates decorated with silver and gold nanoparticles for sensor applications
Authors: Ding Junwei , Zhang Kai , Wei Gang , Su Zhiqiang
Published: August 2015

The PPyNPT–Ag and PPyNPT–Au nanohybrids fabricated by self-assembly process exhibit excellent electrocatalytic activity toward H2O2 and DA, respectively.
Porphyrin containing lipophilic amide groups as a photosensitizer for dye-sensitized solar cells
Authors: Gasiorowski J. , Pootrakulchote N. , Reanprayoon C. , Jaisabuy K. , Vanalabhpatana P. , Sariciftci N. S. , Thamyongkit P.
Published: August 2015

A novel porphyrin containing lipophilic amide groups was synthesized and explored for its use in dye-sensitized solar cells.
A novel biosensor for silver(i) ion detection based on nanoporous gold and duplex-like DNA scaffolds with anionic intercalator
Authors: Zhou Yaoyu , Tang Lin , Zeng Guangming , Zhu Jingjing , Dong Haoran , Zhang Yi , Xie Xia , Wang Jiajia , Deng Yaocheng
Published: August 2015

A novel biosensor for silver(i) ion detection based on nanoporous gold and duplex-like DNA scaffolds with anionic intercalator.
Theoretical model estimation of guest diffusion in metal–organic frameworks (MOFs)
Authors: Zheng B. , Huang K.-W. , Du H.
Published: August 2015

An analytical model was developed to efficiently and accurately estimate the guest diffusivity in flexible metal–organic frameworks (MOFs).
Preparation and application of bacteriophage-loaded chitosan microspheres for controlling Lactobacillus plantarum contamination in bioethanol fermentation
Authors: Lin Xianghua , Han Pei , Dong Shijun , Li Hao
Published: August 2015

The bacteriophage-loaded chitosan microspheres can effectively controlL. plantarumcontamination in bioethanol fermentation. Moreover, sustained release of bacteriophage would enhance the effect of bacteriophage through prolonging the action time.
Dynamic moduli of magneto-sensitive elastomers: a coarse-grained network model
Authors: Ivaneyko Dmytro , Toshchevikov Vladimir , Saphiannikova Marina
Published: August 2015

The viscoelastic properties of magneto-sensitive elastomers (MSEs) in a low-frequency regime are studied using a coarse-grained network model.
In vitro circadian rhythms: imaging and electrophysiology
Authors: Beaulé Christian , Granados-Fuentes Daniel , Marpegan Luciano , Herzog Erik D
Published: August 2015

In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell–cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity.
Mechanisms of adaptation in the intestinal parasite Giardia lamblia
Authors: Lujan Hugo D.
Published: August 2015

Giardia lamblia, a parasite of humans, is a major source of waterborne diarrhoeal disease. Giardia is also an excellent system to study basic biochemical processes because it is a single-celled eukaryote with a small genome and its entire life cycle can be replicated in vitro. Giardia trophozoites undergo fundamental changes to survive outside the intestine of their host by differentiating into infective cysts. Encystation entails the synthesis, processing, transport, secretion and extracellular assembly of cyst wall components. To survive within the intestine, Giardia undergoes antigenic variation, a process by which the parasite continuously switches its major surface molecules, allowing the parasite to evade the host's immune response and produce chronic and recurrent infections. The objective of the present chapter is to provide a better understanding of the molecular mechanisms involved in adaptation and differentiation in Giardia, with a particular focus on the process of encystation and antigenic variation of this interesting micro-organism.
Serum keratan sulphate levels rise in rheumatoid arthritis patients, but fall in ankylosing spondylitis patients compared with normal controls
Authors: WILL ROB , ELSWOOD JUDITH , EDMUNDS LAUREL , CALIN ANDREI
Published: August 2015

Summary

Serum levels of keratan sulphate (KS) were found to be significantly elevated in patients with destructive and predominantly seronegative rheumatoid arthritis (RA) compared with a control population. Levels in RA did not correlate with clinical or laboratory indices of joint activity or damage. Conversely levels were depressed in ankylosing spondylitis (AS) compared with controls.
A progress report on the crystallographic studies on the B800–850 antenna complex from Rhodopseudomonas acidophila strain 10050
Authors: Cogdell Richard J. , Halloren Evelyn , Hawthornthwaite Anna M. , Thunnissen Marjolein M. G. M. , Freer Andy A. , McDermott Gerry , Guthrie Neil , Isaacs Neil , Lindsay J. Gordon , Papiz Miroslav
Published: August 2015

Summary

Large single crystals (up to 1 mm in each dimension) of the B800–850 antenna complex from Rhodopseudomonas acidophila strain 10050 have been grown in the presence of β-octyl-glucoside. These crystals have the space group R32 and unit cell dimensions of a = b = 119.9 Å and c = 297.0 Å. Recently we have improved our crystallization procedures so that all crystals now diffract reliably to beyond 3.5 Å, with some diffracting to below 3 Å. A range of isomorphous heavy atom derivatives have been prepared and we are now engaged in locating the heavy atom sites within the unit cell.
An overview of bioactivation of chemical carcinogens
Authors: Glatt H. R.
Published: August 2015

Most environmental carcinogens require metabolic activation to reactive intermediates and are mutagenic in appropriate test systems. During the last decade, the cDNAs of numerous xenobiotic-metabolizing enzymes have been cloned. The individually expressed enzymes were used to study their substrate specificities and their inhibition by other compounds. Various enzymes were expressed directly in target cells of in vitro mutagenicity tests. This is illustrated in the present study for rat and human sulphotransferases (SULTs) expressed in Salmonella typhimurium TA1538. Numerous compounds were mutagenic in the new test system. Some of these promutagens were activated by several different SULT forms, whereas many other promutagens were activated with high selectivity by a specific enzyme form, but not by genetically closely related forms from the same species (e.g. allelic variants) or orthologous enzymes from other species. Similar findings have been made using recombinant test systems for specific forms of other classes of enzymes (e.g. cytochromes P450). This high selectivity in activation (and inactivation) may explain some organotropisms as well as species and inter-individual differences in the action of carcinogens. Many carcinogen-metabolizing enzymes are induced or inhibited by other xenobiotics. Such interactions can be exploited for chemo-prevention, which however may be carcinogen-and tissue-dependent.
Diet and colorectal cancer prevention
Authors: Bingham S. A.
Published: August 2015

The majority of cancers are sporadic and epidemiological estimates suggest that up to 80% of colorectal cancer is attributable to diet. Epidemiologically, cross-sectional comparisons, case-control studies and trends in food intake show high rates of colorectal cancer in populations consuming diets high in meat and fat, and low in starch, NSP (non-starch polysaccharides, fibre) and vegetables. In general, prospective studies tend to support these findings although estimates of relative risk are not high. Existing prospective studies have however used crude indices of diet subject to substantial measurement error, and interactions with genetic polymorphisms in, for example, phase-1 and -II enzymes have been studied only rarely. The association between meat consumption and colorectal cancer is usually attributed to the formation of heterocyclic amines in meat when it is cooked. In addition, in humans high-meat diets increase the level of nitrosatable material entering the colon so that faecal N-nitroso compounds (NOCs) increase in a dose-responsive manner following endogenous synthesis in the colon. Some of the mutations and guanine adducts accumulated during colorectal cancer progression are characteristic of alkylative damage, which would be compatible with NOC exposure. To date, NSP, resistant starch and vegetables have not reduced faecal NOC levels.
Adipocyte studies: systems for investigating effects of growth hormone and other chronically acting hormones
Authors: Vernon R. G.
Published: August 2015

Adipose tissue is very amenable to study in vitro. Collagenase digestion yields free adipocytes which usually respond well to acute stimulation/inhibition by hormones and other factors. Chronic effects of hormones are best studied using explants of adipose tissue which, from some species (e.g. sheep), can be maintained in culture for up to a week without loss of function. Alternatively, pre-adipocytes can be readily isolated from adipose tissue and induced to proliferate and differentiate in culture, while various adipocyte-like cell-lines have been established, which can be used for chronic studies. Use of these various systems for investigating the mechanisms of action of growth hormone are described.
Decidual natural-killer-cell interaction with trophoblast: cytolysis or cytokine production?
Authors: Loke Y. W. , King A.
Published: August 2015

At the implantation site, the uterine mucosa (decidua) is infiltrated by large numbers of natural killer (NK) cells. These NK cells are in close contact with the invading fetal trophoblast and we have proposed that they might be the effector cells that control the implantation of the allogeneic placenta. Recent characterization of NK cell receptors and their HLA class I ligands has suggested potential mechanisms by which NK cells might interact with trophoblast. However, what happens as a result of this interaction is not clear. The traditional method for investigating NK cell function in vitro is the protection from lysis of target cells by expression of HLA class I antigens. This might not be an accurate reflection of what happens in vivo. Another function of NK cells is the production of cytokines on contact with target cells. This could be an important outcome of the interaction between decidual NK cells and trophoblast. Decidual NK cells are known to produce a variety of cytokines; trophoblast cells express receptors for many of these cytokines, indicating that they can potentially respond. In this way, decidual NK cells have a significant influence on trophoblast behaviour during implantation.
Growth factor-extracellular matrix synergy in the control of trophoblast invasion
Authors: Aplin J. D. , Lacey H. , Haigh T. , Jones C. J. P. , Chen C.-P. , Westwood M.
Published: August 2015

At the periphery of the human placenta, trophoblast attaches to the uterine wall. The tissue interface contains many anchoring sites, with cytotrophoblast columns that form bridges between the overlying extraembryonic (villous) mesenchyme and the maternal decidual stroma beneath. From the periphery of these columns, large numbers of trophoblast cells detach, migrate through the decidua and eventually colonize and transform maternal arteries. In this way the placenta increases and gives priority to the maternal blood supply to the conceptus. We have shown that when early villous tissue is explanted on a collagen gel in serum-free medium, anchoring-site morphogenesis occurs. Thus, in the presence of placental mesenchyme but in the absence of maternal cells, contact with a permissive extracellular matrix (ECM) is necessary and sufficient for cytotrophoblast column development. Proliferation of trophoblast occurs, followed by differentiation into a columnar cell phenotype in which cells remain attached to one another and to the ECM. At this stage, interaction between fibronectin and integrin α5β1 at the cell surface stabilizes the column and the cells remain as a contiguous multilayered sheet. However, the addition of serum-free conditioned medium from first-trimester placental fibroblasts stimulates cytotrophoblast to detach from the distal column and migrate in streams across the ECM. The removal of insulin-like growth factor I (IGF-I) from the fibroblast medium decreases streaming activity, whereas the addition of exogenous IGF-I (10 ng/ml) to serum-free medium produces a streaming phenotype. In contrast, transforming growth factor β1 (10 ng/ml) maintains the cells in a tight sheet. These results suggest the possibility of a paracrine interaction between villous mesenchyme and cytotrophoblast in anchoring sites to stimulate the infiltration of the maternal ECM by trophoblast. Such a mechanism would be self-limiting because the signal diminishes with distance from the placenta.
HLA-G in the human placenta: expression and potential functions
Authors: Bouteiller P. Le
Published: August 2015

HLA-G is a non-classical class I molecule specifically expressed in the placenta, suggesting that it might have a physiological function at the materno-foetal interface. The structural characteristics of HLA-G, the placental pattern of expression and the functional properties of this class Ib glycoprotein in vitro are described and evaluated in the context of pregnancy. The possible anti-viral function of HLA-G, its modulatory role of natural killer cell activity and its likely nonimmunological functions are discussed.
Genetic analysis of insulin-like growth factor II and HLA-G in pre-eclampsia
Authors: Bermingham J. , Jenkins D. , McCarthy T. , O'Brien M.
Published: August 2015

Pre-eclampsia (PE) is uniquely a disease of pregnancy and is the major cause of foetal and maternal morbidity and mortality. Epidemiological studies show that PE is highly heritable, with a high incidence in all populations. The underlying pathology indicates that absent or shallow invasion of foetal trophoblasts into maternal arteries is a feature of true PE. The objective of this study was to determine the genetic factors influencing PE. A large number of mother-father-baby trios were collected in which the first pregnancy was complicated by severe PE. After careful examination of the epidemiology and pathology of the disease, two plausible candidate genes, namely insulin-like growth factor II (IGF-II) and HLA-G, were analysed for association with PE. No association was found between a commonly occurring polymorphism in IGF-II and PE. Three polymorphisms in HLA-G were analysed in the sample cohorts. No association was found between three polymorphisms in HLA-G and PE. However, the frequency of the HLA-G insertion/deletion polymorphism in exon 8 deviated significantly from Hardy-Weinberg expectations in PE off-spring, reflecting an excess of heterozygotes for these polymorphisms in PE offspring. The significance of this deviation is not clear and further genetic analysis will be necessary to confirm this finding and to explore further the candidacy of HLA-G in PE.
Regulation of cell cycle re-entry by growth, survival and stress signalling pathways
Authors: Cook S.J. , Balmanno K. , Garner A. , Millar T. , Taverner C. , Todd D.
Published: August 2015

The mitogen-activated and stress-activated protein kinases transduce signals from plasma membrane signalling machinery into the nucleus to modulate gene expression. By regulating the genomic response to environmental cues (growth factors, stresses) these pathways determine whether a cell re-enters the cell cycle, undergoes cell cycle arrest, senescence or apoptosis. We are particularly interested in how these pathways integrate with each other, and interact with the cell cycle machinery to achieve these discrete biological responses.
Telomere diminution as a cause of immune failure in old age: an unfashionable demurral
Authors: Miller R. A.
Published: August 2015

The hypothesis that cellular proliferation leads to telomere shortening, which in turn leads to replicative failure, which in turn leads to a failure of immune function in aged individuals, is here evaluated against the published evidence about the nature and pace of immune decline in animals and humans. Although the evidence is strong that telomere shortening in late-passage human lymphocyte and non-lymphocytic cell lines induces a state in which the cells can no longer divide, there is no compelling evidence to suggest that replicative senescence of this kind is an important contributor to immune deficiency in old age. On the contrary, the accelerated pace of immune decline in mice and rats, whose telomeres are much longer than those of humans, argues strongly that the factors that pace age-dependent immune decline do not include telomere shortening. In addition, three subsidiary arguments - (a) the decline with age in naive T cell proliferation despite their relatively long telomeres; (b) the preservation of T cell proliferation in Werner's syndrome patients despite their cell lines' proclivity to replicative senescence in vitro; and (c) the ability of PMA and ionomycin to stimulate proliferation in T cells from old donors, but not in late-passage T cell lines - all support the conclusion that aging of the immune system in living animals is not a consequence of the kind of replicative senescence typically caused by short telomeres in vitro.
Measurement of telomere length in haematopoietic cells using in situ hybridization techniques
Authors: Martens U. M. , Brass V. , Engelhardt M. , Glaser S. , Waller C. F. , Lange W. , Schmoor C. , Poon S. S. S. , Lansdorp P. M.
Published: August 2015

The DNA of human chromosomes terminates in several kilobases of telomere repeats that are gradually lost with age and with replication in vitro. Defective telomere maintenance has been shown to be causally linked to cell cycle exit and apoptosis. In order to overcome the limitations imposed by Southern blotting, we have established a quantitative fluorescence in situ hybridization (Q-FISH) technique. This technique allows estimation of telomere length in specific chromosome arms from metaphase cell preparations. Furthermore, we have extended quantitative in situ hybridization to flow cytometry (flow FISH) in order to obtain information on the mean telomere repeat content in suspended cells. Telomere length in granulocytes, monocytes, CD8 and CD4 T lymphocytes and natural killer cells was found to differ slightly in the peripheral blood of adults. However, strikingly longer telomeres were observed in B lymphocytes (∼ 1.3 kb longer), suggesting a functional role for telomere maintenance in this cell subset. In summary, Q-FISH and flow FISH represent new methods for measuring telomere length in single cells and allow studies of telomere dynamics in haematopoietic subpopulations at various stages of normal and abnormal antigen responses.
The Chemical and Biological Versatility of Riboflavin
Authors: Massey V.
Published: August 2015

Since their discovery and chemical characterization in the 1930s, flavins have been recognized as being capable of both one- and two-electron transfer processes, and as playing a pivotal role in coupling the two-electron oxidation of most organic substrates to the one-electron transfers of the respiratory chain. In addition, they are now known as versatile compounds that can function as electrophiles and nucleophiles, with covalent intermediates of flavin and substrate frequently being involved in catalysis. Flavins are thought to contribute to oxidative stress through their ability to produce superoxide, but at the same time flavins are frequently involved in the reduction of hydroperoxides, products of oxygen-derived radical reactions. Flavoproteins play an important role in soil detoxification processes via the hydroxylation of many aromatic compounds, and a simple flavoprotein in liver microsomes catalyses many reactions similar to those carried out by cytochrome P450 enzymes. Flavins are involved in the production of light in bioluminescent bacteria, and are intimately connected with light-initiated reactions such as plant phototropism and nucleic acid repair processes. Recent reports also link them to programmed cell death. The chemical versatility of flavoproteins is clearly controlled by specific interactions with the proteins with Which they are bound. One of the main thrusts of current research is to try to define the nature of these interactions, and to understand in chemical terms the various steps involved in catalysis by flavoprotein enzymes.
Inductive activity of recombinant human growth and differentiation factor-5
Authors: Spiro R. C. , Liu L.-S. , Heidaran M. A. , Thompson A. Y. , Ng C. K. , Pohl J. , Poser J. W.
Published: August 2015

Growth and differentiation factor-5 (GDF-5) is a divergent member of the transforming growth factor-β/bone morphogenetic protein (BMP) superfamily that is required for proper skeletal patterning and development in the vertebrate limb. Based on the homology of GDF-5 with other bone-inducing BMP family members, the inductive activity of a recombinant form of human GDF-5 (rhGDF-5) was evaluated in a series of in vitro assays and in vivo bone-formation models. The in vitro response to rhGDF-5 resulted in the formation of chondrogenic nodules in fetal rat calvarial cells cultured in the context of collagen or collagen/hyaluronate extracellular matrices. Matrices loaded with rhGDF-5 induced ectopic cartilaginous and osseous tissue when implanted in subcutaneous or intramuscular sites. In non-human primate long-bone-defect and spinal-fusion models, rhGDF-5 combined with a mineralized collagen matrix induced bone formation in a manner equivalent to autogenous bone. These results highlight the unique potential of rhGDF-5 in a wide variety of orthopaedic applications.
Modulation of thyroid hormone receptor silencing function by co-repressors and a synergizing transcription factor
Authors: Lutz M. , Baniahmad A. , Renkawitz R.
Published: August 2015

We have found that the thyroid hormone receptor (T3R) functionally synergizes with the CCCTC-binding factor (CTCF). CTCF is a highly conserved zinc-finger protein that has been connected with multiple functions in gene regulation including chromatin insulator activity, transcriptional enhancement and silencing as well as tumour suppression. A specific property of CTCF is that some of the binding sites are found in the vicinity of T3R-binding sites. Interestingly, both factors synergize in repression as well as in activation. T3R-mediated repression has been shown to involve co-repressors such as the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), N-CoR or Alien. These co-repressors in turn have been found to interact with Sin3A. Until now, the mechanisms by which CTCF synergizes with T3R in transcriptional repression has not been determined. Here we show that CTCF comprises autonomous silencing domains that mediate transcriptional repression when tethered to a promoter sequence. At least one of these domains, the zinc-finger region of CTCF, binds Sin3A without binding to SMRT or N-CoR and recruits histone deacetylation activity. For Sin3A we identified two different domains interacting independently with the CTCF zinc-finger cluster. The ability of regions of CTCF to retain deacetylase activity is correlated with the ability to bind to Sin3A and to repress transcription. Taking these results together, the synergy in repression mediated by T3R and CTCF might be achieved by the binding of multiple molecules of Sin3A to the T3R/CTCF-DNA complex, thus providing a large platform for the recruitment of histone deacetylases.
Endothelin-converting enzyme-like I (ECEL1; ‘XCE’): a putative metallopeptidase crucially involved in the nervous control of respiration
Authors: Valdenaire O. , Schweizer A.
Published: August 2015

Endothelin-converting enzyme-like 1 (ECEL1) is a putative zinc metalloprotease that was recently identified on the basis of its strong similarity to endothelin-converting enzyme 1. The physiological function of ECEL1 remains unknown so far; the failure to identify a substrate for ECEL1 could be related to the endoplasmic reticulum subcellular localization found by immunofluorescence in recombinant systems. However, clues to the function of ECEL1 were provided by the in-activation of its gene in mice, which resulted in neonatal lethality. The phenotype of homozygous ECEL1− mice, together with the very specific expression profile of its mRNA in the central nervous system, suggests that ECEL1 is crucially involved in the nervous control of respiration.
Exploring the Caenorhabditis elegans and Drosophila melanogaster genomes to understand neuropeptide and peptidase function
Authors: Coates D. , Siviter R. , Isaac R. E.
Published: August 2015

Comparison of peptidase gene families in the newly released Drosophila melanogaster and Caenorhabditis elegans genomes highlights important differences in peptidase distributions with relevance to the evolution of both form and function in these two organisms and can help to identify the most appropriate model when using comparative studies relevant to the human condition.
Recognition of multiple drugs by a single protein: a trivial solution of an old paradox
Authors: Vazquez-Laslop N. , Zheleznova E. E. , Markham P. N. , Brennan R. G. , Neyfakh A. A.
Published: August 2015

Multi drug-efflux transporters recognize scores of structurally dissimilar toxic compounds and expel them from cells. The broad chemical specificity of these transporters challenges some of the basic dogmas of biochemistry and remains unexplained. To understand, at least in principle, how a protein can recognize multiple compounds, we analysed the transcriptional regulator of the Bacillus subtilis multidrug transporter Bmr. This regulator, BmrR, binds multiple dissimilar hydrophobic cations and, by activating the expression of the Bmr transporter, causes their expulsion from the cell. Crystallographic analysis of the complexes of the inducer-binding domain of BmrR with some of its inducers revealed that ligands cause disordering of the surface α-helix and penetrate the hydrophobic core of the protein, where they form multiple van der Waals and stacking interactions with hydrophobic amino acids and an electrostatic bond with the buried glutamic residue. Mutational analysis of the binding site suggests that each ligand forms a unique set of atomic contacts with the protein: each tested mutation exerted disparate effects on the binding of different ligands. The example of BmrR demonstrates that a protein can bind multiple compounds with micromolar affinities by using only electrostatic and hydrophobic interactions. Its ligand specificity can be broadened by the flexibility of the binding site. It therefore seems that the commonly expressed fascination with the broad specificity of multidrug transporters is misdirected and originates from an almost exclusive familiarity with the more sophisticated processes of specific molecular recognition that predominate among existing proteins.
Kinetics of mRNA polyadenylation and its relation to transcription termination in eukaryotes
Authors: Jamil Amer , Martinson Harold G.
Published: August 2015

Processing of most eukaryotic mRNAs includes and polyadenylation of the nascent transcript. Until now there has been no method for the reliable measurement of these processes in vivo. Therefore, in the present work a new technique was developed for measuring precisely the rate of cleavage and polyadenylation in vivo. The method uses a cis-antisense element targeted to an upstream poly (A) signal. Duplex formation of the antisense element with the poly (A) signal region prevents polyadenylation. In a series of expression vector constructs the antisense element was moved increasing distances downstream of its target poly (A) site, reasoning that if it takes the polymerase longer to reach the antisense element, polyadenylation would have more time to occur. Using this method the half time for commitment to cleavage and polyadenylation at the SV40 early poly (A) site and SPA (synthetic poly A site) was found to be 5 seconds. It was found that strong sites (SV 40 late poly (A) site) were processed faster. Commitment to cleavage and polyadenylation was found to be a multistep process. The expression results were confirmed with the help of RNase protection assay. Relationship between polyadenylation and transcription termination was also studied by using G-free assay and found to be positively correlated. Present data support looping moded suggesting some communication exists between polyadenylation complex and RNA pol. II for transcription termination.
Rho GTPases and the control of cell behaviour
Authors: Hall A.
Published: August 2015

Rho, Rac and Cdc42, three members of the Rho family of small GTPases, each control a signal transduction pathway linking membrane receptors to the assembly and disassembly of the actin cytoskeleton and of associated integrin adhesion complexes. Rho regulates stress fibre and focal adhesion assembly, Rac regulates the formation of lamellipodia protrusions and membrane ruffles, and Cdc42 triggers filopodial extensions at the cell periphery. These observations have led to the suggestion that wherever filamentous actin is used to drive a cellular process, Rho GTPases are likely to play an important regulatory role. Rho GTPases have also been reported to control other cellular activities, such as the JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) cascades, an NADPH oxidase enzyme complex, the transcription factors NF-κB (nuclear factor κB) and SRF (serum-response factor), and progression through G1 of the cell cycle. Thus Rho, Rac and Cdc42 can regulate the actin cytoskeleton and gene transcription to promote co-ordinated changes in cell behaviour. We have been analysing the biochemical contributions of Rho GTPases in cell movement and have found that Rac controls cell protrusion, while Cdc42 controls cell polarity.
Simulation studies of the interactions between membrane proteins and detergents
Authors: Bond P.J. , Cuthbertson J. , Sansom M.S.P.
Published: August 2015

Interactions between membrane proteins and detergents are important in biophysical and structural studies and are also biologically relevant in the context of folding and transport. Despite a paucity of high-resolution data on protein–detergent interactions, novel methods and increased computational power enable simulations to provide a means of understanding such interactions in detail. Simulations have been used to compare the effect of lipid or detergent on the structure and dynamics of membrane proteins. Moreover, some of the longest and most complex simulations to date have been used to observe the spontaneous formation of membrane protein–detergent micelles. Common mechanistic steps in the micelle self-assembly process were identified for both α-helical and β-barrel membrane proteins, and a simple kinetic mechanism was proposed. Recently, simplified (i.e. coarse-grained) models have been utilized to follow long timescale transitions in membrane protein–detergent assemblies.
Leptin: a potential cognitive enhancer?
Authors: Harvey J. , Shanley L.J. , O'Malley D. , Irving A.J.
Published: August 2015

It is well documented that the hormone leptin signals information regarding the status of fat stores to hypothalamic nuclei, which in turn control feeding behaviour and body weight. However, leptin and its receptor are widely expressed in many extra-hypothalamic brain regions, including hippocampus, brain stem and cerebellum. Moreover, evidence is accumulating that leptin has other neuronal functions that are unrelated to its effects on energy homeostasis. Indeed a role for leptin in neuronal development has been suggested as leptin-deficient rodents display abnormal brain development and leptin actively participates in the development of the hypothalamus. In the hippocampus, leptin is a potential cognitive enhancer as genetically obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Moreover, direct administration of leptin into the hippocampus can facilitate hippocampal LTP (long-term potentiation) in vivo and improve memory processing in mice. At the cellular level, we have also shown that leptin has the capacity to convert short-term potentiation into LTP. Here, we review the data that leptin influences hippocampal synaptic plasticity via enhancing NMDA (N-methyl-D-aspartate) receptor function. We also provide evidence that rapid trafficking of NMDA receptors to the plasma membrane may underlie the effects of leptin on excitatory synaptic strength.
Using genomic and lipidomic strategies to investigate sphingolipid function in the yeast heat-stress response
Authors: Cowart L.A. , Hannun Y.A.
Published: August 2015

In addition to their crucial role in membrane structure in Saccharomyces cerevisiae, sphingolipids serve vital roles in various aspects of yeast biology including endocytosis, intracellular protein transport and stress responses. Although previous studies have unequivocally demonstrated the sphingolipid requirements for these processes, few studies have contributed mechanistic information. We have used a systems approach including microarray, lipidomics and metabolic modelling to better understand (i) biochemical relationships between various branches of sphingolipid metabolism and pathways and contributing pathways such as fatty acid metabolism and phospholipid synthesis, (ii) the changes in cellular sphingolipid composition under various conditions and (iii) the effects of these changes on the transcriptional profiles and subsequently, cell phenotypes. Thus far, these approaches have indicated roles for sphingolipids in major transcriptional changes in response to heat stress, carbon source utilization, sporulation, cell wall integrity and other basic cellular functions. Although the yeast genome is fully sequenced, nearly 50% of all transcribed open reading frames remain uncharacterized with regard to cellular function; therefore, a major advantage of this approach is the ability to identify both biochemical and biological roles for enzymes and their products within broad cellular contexts.
Interactions of the ergosterol biosynthetic pathway with other lipid pathways
Authors: Veen M. , Lang C.
Published: August 2015

Micro-organisms have recently received broad attention as sources of novel lipids. An increased understanding of the effects of fats and oils and their composition on the metabolism and on health has shifted the focus towards the use of lipids for disease treatment and prevention and for the promotion of good health. A large range of lipidic products produced by yeast is known today. Ergosterol and its metabolic precursors are major lipidic components of industrial and commercial interest. Having in mind the aim to increase the productivity of ergosterol and its precursor metabolites, both the knowledge of regulatory mechanisms of the biosynthetic pathway and its interactions with other lipid pathways like those of sphingolipids, phospholipids and fatty acids are crucial.
Regulation of sterol metabolism in Candida albicans by the UPC2 gene
Authors: White T.C. , Silver P.M.
Published: August 2015

Candida albicans is an important pathogenic fungus of humans, causing a range of infections. These infections are usually treated with antifungal drugs that target sterol metabolism. Resistance to these antifungals can result from overexpression of sterol biosynthetic genes. Therefore it is of interest to understand transcriptional regulation of sterol biosynthesis in C. albicans. Recently two reports [Silver, Oliver and White (2004) Eukaryot. Cell 3, 1391–1397; MacPherson, Akache, Weber, De Deken, Raymond and Turcotte (2005) Antimicrob. Agents Chemother. 49, 1745–1752] have identified and characterized a single C. albicans transcription factor gene UPC2 that regulates sterol metabolism. The details of both characterizations are compared and contrasted. These reports extend our understanding of sterol regulation in this important human pathogen.
Compartmentalized cAMP signalling regulates vasopressin-mediated water reabsorption by controlling aquaporin-2
Authors: Henn V. , Stefan E. , Baillie G.S. , Houslay M.D. , Rosenthal W. , Klussmann E.
Published: August 2015

The cAMP/PKA (protein kinase A) signalling pathway is activated by a plethora of stimuli. To facilitate the specificity of a cellular response, signal transduction complexes are formed and segregated to discrete sites (compartmentalization). cAMP/PKA signalling compartments are maintained by AKAPs (A-kinase anchoring proteins) which bind PKA and other signalling proteins, and by PDEs (phosphodiesterases). The latter hydrolyse cAMP and thus limit its diffusion and terminate PKA activity. An example of a cAMP-dependent process requiring compartmentalization of cAMP/PKA signals is arginine-vasopressin-regulated water reabsorption in renal principal cells. A detailed understanding of the protein interactions within a signal transduction complex offers the possibility to design agents influencing PKA binding to a specific AKAP, the targeting of an AKAP or the interactions of AKAPs with other signalling molecules. The ability to specifically modulate selected branches of a signal transduction pathway would greatly advance basic research, and may lead to new drugs suitable for the treatment of diseases caused by dysregulation of anchored PKA signalling (e.g. renal and cardiovascular diseases).
AMPA receptor phosphorylation during synaptic plasticity
Authors: Boehm J. , Malinow R.
Published: August 2015

A widely studied example of vertebrate plasticity is LTP (long-term potentiation), the persistent synaptic enhancement that follows a brief period of coinciding pre- and post-synaptic activity. During LTP, different kinases, including CaMKII (calcium/calmodulin-dependent protein kinase II) and protein kinase A, become activated and play critical roles in induction and maintenance of enhanced transmission. Biochemical analyses have revealed several regulated phosphorylation sites in the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits, GluR1 and GluR4. The regulated insertion of these receptors is a key event in the induction of LTP. Here, we discuss the phosphorylation of GluR1 and GluR4 and its role in receptor delivery and neuronal plasticity.
Critical role of acylglycerol kinase in epidermal growth factor-induced mitogenesis of prostate cancer cells
Authors: Spiegel S. , Milstien S.
Published: August 2015

The bioactive phospholipids, LPA (lysophosphatidic acid) and PA (phosphatidic acid), regulate pivotal processes related to the pathogenesis of cancer. Recently, we cloned a novel type of lipid kinase that phosphorylates monoacylglycerols (such as 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand) and diacylglycerols, to form LPA and PA, respectively. This AGK (acylglycerol kinase) is highly expressed in prostate cancer cell lines and the results reviewed here suggest that AGK might be a critical player in the initiation and progression of prostate cancer. Intriguingly, down-regulation of endogenous AGK inhibited EGF (epidermal growth factor), but not LPA-induced ERK1/2 (extracellular-signal-regulated kinase 1/2) activation and progression through the S-phase of the cell cycle. In this review, we will summarize the evidence demonstrating that AGK amplifies EGF growth signalling pathways that play an important role in the pathophysiology of prostate cancer. Because LPA has long been implicated as an autocrine and paracrine growth stimulatory factor for prostate cancer cells, the identification of this novel lipid kinase that regulates its production could provide new and useful targets for preventive or therapeutic measures.
Making crossovers during meiosis
Authors: Whitby M.C.
Published: August 2015

Homologous recombination (HR) is required to promote both correct chromosome segregation and genetic variation during meiosis. For this to be successful recombination intermediates must be resolved to generate reciprocal exchanges or ‘crossovers’ between the homologous chromosomes (homologues) during the first meiotic division. Crossover recombination promotes faithful chromosome segregation by establishing connections (chiasmata) between the homologues, which help guide their proper bipolar alignment on the meiotic spindle. Recent studies of meiotic recombination in both the budding and fission yeasts have established that there are at least two pathways for generating crossovers. One pathway involves the resolution of fully ligated four-way DNA junctions [HJs (Holliday junctions)] by an as yet unidentified endonuclease. The second pathway appears to involve the cleavage of the precursors of ligated HJs, namely displacement (D) loops and unligated/nicked HJs, by the Mus81-Eme1/Mms4 endonuclease.
Calcium, mitochondria and reperfusion injury: a pore way to die
Authors: Halestrap A.P.
Published: August 2015

When mitochondria are exposed to high Ca2+ concentrations, especially when accompanied by oxidative stress and adenine nucleotide depletion, they undergo massive swelling and become uncoupled. This occurs as a result of the opening of a non-specific pore in the inner mitochondrial membrane, known as the MPTP (mitochondrial permeability transition pore). If the pore remains open, cells cannot maintain their ATP levels and this will lead to cell death by necrosis. This article briefly reviews what is known of the molecular mechanism of the MPTP and its role in causing the necrotic cell death of the heart and brain that occurs during reperfusion after a long period of ischaemia. Such reperfusion injury is a major problem during cardiac surgery and in the treatment of coronary thrombosis and stroke. Prevention of MPTP opening either directly, using agents such as cyclosporin A, or indirectly by reducing oxidative stress or Ca2+ overload, provides a protective strategy against reperfusion injury. Furthermore, mice in which a component of the MPTP, CyP-D (cyclophilin D), has been knocked out are protected against heart and brain ischaemia/reperfusion. When cells experience a less severe insult, the MPTP may open transiently. The resulting mitochondrial swelling may be sufficient to cause release of cytochrome c and activation of the apoptotic pathway rather than necrosis. However, the CyP-D-knockout mice develop normally and show no protection against a range of apoptotic stimuli, suggesting that the MPTP does not play a role in most forms of apoptosis.