bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased prevalence of cardiovascular defects among 56,709 California twin pairs
Authors: Hardin J. , Carmichael S.L. , Selvin S. , Lammer E.J. , Shaw G.M.
Published: April 2009

This study compared the prevalence of cardiovascular defects in twin and singleton births and explored the influences of zygosity (monozygotic and dizygotic) and maternal age (<35 and ≥35 years of age) on concordance. Data on twin and singleton infants with (n = 628 twin pairs and n = 14,078 singletons) and without (n = 53,974 twin pairs and n = 4,858,255 singletons) cardiovascular defects were obtained from the California Birth Defects Monitoring Program and the California vital statistics birth and fetal death records during the period 1983–2003. Prevalence ratios (PR) (prevalence of twin/singleton) and approximate 95% confidence intervals were calculated for 16 congenital cardiovascular categories. Poisson regression techniques using log‐linear models were employed to assess whether the probability of concordance of defects within each cardiovascular category varied by zygosity or maternal age. An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like‐sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins. Our study provides evidence that twinning is associated with more cardiovascular defects than singletons. Increased concordance for flow lesions in monozygotic twins was observed, an observation that is in agreement with findings from familial recurrence studies of cardiovascular defects. © 2009 Wiley‐Liss, Inc.
Pure monosomy and pure trisomy of 13q21.2–31.1 consequent to a familial insertional translocation: Exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1)
Authors: Grati Francesca R. , Lesperance Marci M. , De Toffol Simona , Chinetti Sara , Selicorni Angelo , Emery Sarah , Grimi Beatrice , Dulcetti Francesca , Malvestiti Barbara , Taylor Joseph , Milani Silvia , Ruggeri Anna M. , Maggi Federico , Simoni Giuseppe
Published: April 2009

Insertional translocations (IT) are rare structural rearrangements. Offspring of IT balanced carriers are at high risk to have either pure partial trisomy or monosomy for the inserted segment as manifested by “pure” phenotypes. We describe an IT between chromosomes 3 and 13 segregating in a three‐generation pedigree. Short tandem repeat (STR) segregation analysis and array‐comparative genomic hybridization were used to define the IT as a 25.1 Mb segment spanning 13q21.2–q31.1. The phenotype of pure monosomy included deafness, duodenal stenosis, developmental and growth delay, vertebral anomalies, and facial dysmorphisms; the trisomy was manifested by only minor dysmorphisms. As the AUNA1 deafness locus on 13q14‐21 overlaps the IT in the PCDH9 (protocadherin‐9) gene region, PCDH9 was investigated as a candidate gene for deafness in both families. Genotyping of STRs and single nucleotide polymorphisms defined the AUNA1 breakpoint as 35 kb 5′ to PCDH9, with a 2.4 Mb area of overlap with the IT. DNA sequencing of coding regions in the AUNA1 family and in the retained homologue chromosome in the monosomic patient revealed no mutations. We conclude that AUNA1 deafness does not share a common etiology with deafness associated with monosomy 13q21.2–q31.3; deafness may result from monosomy of PCHD9 or another gene in the IT, as has been demonstrated in contiguous gene deletion syndromes. Precise characterization of the breakpoints of the translocated region is useful to identify which genes may be contributing to the phenotype, either through haploinsufficiency or extra dosage effects, in order to define genotype–phenotype correlations. © 2009 Wiley‐Liss, Inc.
Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis
Authors: Beaudry Veronica G. , Pathak Navneeta , Koster Maranke I. , Attardi Laura D.
Published: April 2009

Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay–Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell–cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC‐patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC. © 2009 Wiley‐Liss, Inc.
NR2F1 deletion in a patient with a de novo paracentric inversion, inv(5)(q15q33.2), and syndromic deafness
Authors: Brown Kerry K. , Alkuraya Fowzan S. , Matos Michael , Robertson Richard L. , Kimonis Virginia E. , Morton Cynthia C.
Published: April 2009

In an effort to discover genes important for human development, we have ascertained patients with congenital anomalies and cytogenetically balanced chromosomal rearrangements. Herein, we report a 4‐year‐old girl with profound deafness, a history of feeding difficulties, dysmorphism, strabismus, developmental delay, and an apparently balanced de novo paracentric chromosome 5 inversion, inv(5)(q15q33.2). Molecular cytogenetic analysis of the inversion revealed the presence of microdeletions of approximately 400–500 kb at or near both breakpoints. The 5q15 microdeletion completely removes the nuclear receptor NR2F1 (COUP‐TFI) from the inverted chromosome 5. We propose haploinsufficiency of NR2F1 to be the cause of the patient's deafness and many of the other associated anomalies based on striking similarity with the Nr2f1 null mouse. Additionally, this study further highlights the need for high resolution analysis of clinical samples with chromosomal rearrangements as associated deletions may be primarily responsible for the clinical features of these patients. © 2009 Wiley‐Liss, Inc.
Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: Further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion
Authors: Faivre L. , Collod‐Beroud G. , Callewaert B. , Child A. , Loeys B.L. , Binquet C. , Gautier E. , Arbustini E. , Mayer K. , Arslan‐Kirchner M. , Kiotsekoglou A. , Comeglio P. , Grasso M. , Beroud C. , Bonithon‐Kopp C. , Claustres M. , Stheneur C. , Bouchot O. , Wolf J.E. , Robinson P.N. , Adès L. , De Backer J. , Coucke P. , Francke U. , De Paepe A. , Boileau C. , Jondeau G.
Published: April 2009

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with “other type I fibrillinopathy.” In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete “clinical” international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24–32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort. © 2009 Wiley‐Liss, Inc.
Coupling Microdroplet Microreactors with Mass Spectrometry: Reading the Contents of Single Droplets Online
Authors: Fidalgo Luis M. , Whyte Graeme , Ruotolo Brandon T. , Benesch Justin L. P. , Stengel Florian , Abell Chris , Robinson Carol V. , Huck Wilhelm T. S.
Published: April 2009

Voll integriert: Massenspektrometrie (MS) wurde in ein Detektionsschema für Mikrotröpfchen integriert, die in Mikrofluidik‐Kanälen generiert werden (siehe Bild; Maßstab 200 μm). Diese Technik ermöglicht die Identifizierung von Tröpfchen anhand der darin enthaltenen Verbindungen und kombiniert Fluoreszenz‐Screening mit MS‐Analyse. Ähnliche Ansätze könnten genutzt werden, um Proteinevolution und chemische Synthesen auf einem Chip zu realisieren.

magnified image
Iridium Catalysis for CH Bond Arylation of Heteroarenes with Iodoarenes
Authors: Join Benoît , Yamamoto Takuya , Itami Kenichiro
Published: April 2009

Effiziente Kupplungen äquimolarer Mengen der Kupplungspartner und mehrfache C‐H‐Arylierungen gelingen mit einem Ir‐basierten Katalysesystem für die C‐H‐Arylierung elektronenreicher Heteroarene mit Iodarenen zum Aufbau ausgedehnter π‐Systeme. Ein drastischer Einfluss des Liganden auf die Effizienz der Reaktion führte zur Erkenntnis, dass der Crabtree‐Katalysator (siehe Schema; Cy=Cyclohexyl, Py=Pyridin) die optimale Katalysatorvorstufe ist.

magnified image
Ein sphärisches Molekül mit einem Kohlenstoff‐freien Ih‐C80‐topologischen Gerüst
Authors: Scheer Manfred , Schindler Andrea , Gröger Christian , Virovets Alexander V. , Peresypkina Eugenia V.
Published: April 2009

Der vollständige Einschluss des ortho‐Carborans durch ein Fulleren‐artiges Bausteinsystem aus Pentaphosphaferrocen und CuICl führt zur Bildung des sphärischen Supermoleküls C2B10H12§[{Cp*Fe(η5‐P5)}12(CuCl)20]. Dieses Produkt einer templatkontrollierten Aggregation ist das erste Kohlenstoff‐freie C80‐Analogon mit Ikosaedersymmetrie.

magnified image
Physical Biology.From Atoms to Medicine. Herausgegeben von Ahmed Zewail.
Authors: Chergui Majed
Published: April 2009

Imperial College Press, 2008. 584 S., geb., $ 78.00.—ISBN 978‐1848162006

magnified image
Olive‐Shaped Chiral Supramolecules: Simultaneous Self‐Assembly of Heptameric Lanthanum Clusters and Carbon Dioxide Fixation
Authors: Tang Xiao‐Liang , Wang Wen‐Hua , Dou Wei , Jiang Jie , Liu Wei‐Sheng , Qin Wen‐Wu , Zhang Guo‐Lin , Zhang Hong‐Rui , Yu Kai‐Bei , Zheng Li‐Min
Published: April 2009

Kohlendioxid gefasst: Sechs chirale reduzierte Schiff‐Basen mit Aminosäureeinheiten und sieben LaIII‐Ionen bilden mithilfe des CO32−‐Ions ein neuartiges heptameres Lanthan‐Übermolekül (siehe Bild). Der Cluster liegt ausschließlich als chirale Tripelhelix vor. Das CO32−‐Ion, das sich von Luft‐CO2 ableitet, verbrückt in einer seltenen μ3‐dreizähnigen Koordination drei LaIII‐Ionen, womit der Cluster effizient CO2 fixieren kann.

magnified image
Titelbild: A Phosphorus Analogue of Bis(η4‐cyclobutadiene)iron(0) (Angew. Chem. 17/2009)
Authors: Wolf Robert , Slootweg J. Chris , Ehlers Andreas W. , Hartl František , de Bruin Bas , Lutz Martin , Spek Anthony L. , Lammertsma Koop
Published: April 2009

Ein Phosphoranalogon des Komplexes Bis(η4‐cyclobutadien)eisen(0) wird von K. Lammertsma et al. in ihrer Zuschrift auf S. 3150 ff. vorgestellt. Im Hintergrund des Titelbilds posiert John Montagu (1718–1792), 4th Earl of Sandwich und Erster Lord der Admiralität, der es sich sicherlich nicht hätte träumen lassen, dass eines Tages eine wichtige Klasse von Organometallverbindungen nach ihm benannt werden würde. Die Synthese von [Fe(P2C2tBu2)2] belegt, dass die Sandwich‐Komplexe immer noch ein aktuelles Forschungsgebiet sind.

magnified image
Innentitelbild: Synthesis and Biological Activity of Argiotoxin 636 and Analogues: Selective Antagonists for Ionotropic Glutamate Receptors (Angew. Chem. 17/2009)
Authors: Nelson Jared K. , Frølund Sidsel U. , Tikhonov Dennis B. , Kristensen Anders S. , Strømgaard Kristian
Published: April 2009

Spinnen der Gattung Argiope beispielsweise die Argiope lobata, setzen giftige Polyamine ein, die Glutamat‐Rezeptoren stark, aber nicht selektiv blockieren. Geringfügige Änderungen an der Struktur der nativen Toxine, wie sie K. Strømgaard et al. in ihrer Zuschrift auf S. 3133 ff. beschreiben, induzieren eine Selektivität für bestimmte Rezeptor‐Unterarten.

magnified image
Palladium‐Catalyzed Insertion of α‐Diazoesters into Vinyl Halides To Generate α,β‐Unsaturated γ‐Amino Esters
Authors: Kudirka Romas , Devine Sean K. J. , Adams Christopher S. , Van Vranken David L.
Published: April 2009

As easy as 1, 2, 3: A palladium‐catalyzed three‐component coupling generates α,β‐unsaturated γ‐amino acids in a single step (see scheme). The reaction is believed to involve migration of a vinyl substituent to a highly electrophilic palladium carbene. Unlike previous synthetic approaches, this synthesis provides access to γ‐amino acids with non‐natural side chains.

magnified image
Coupling Microdroplet Microreactors with Mass Spectrometry: Reading the Contents of Single Droplets Online
Authors: Fidalgo Luis M. , Whyte Graeme , Ruotolo Brandon T. , Benesch Justin L. P. , Stengel Florian , Abell Chris , Robinson Carol V. , Huck Wilhelm T. S.
Published: April 2009

Fully integrated: Mass spectrometry has been integrated into a detection scheme for microdroplets that are created within microfluidic channels (see picture, scale bar 200 μm). This technique allows droplets to be identified based on the compounds they contain, and combines fluorescence screening with MS analysis. These experiments indicate how similar approaches can be applied to the ambitious goals of on‐chip protein evolution and chemical synthesis.

magnified image
Unusual Interlocking and Interpenetration Lead to Highly Porous and Robust Metal–Organic Frameworks
Authors: Ma Liqing , Lin Wenbin
Published: April 2009

Stop the breathing: As the organic bridging ligands become more elaborate and large, the resulting MOFs tend to experience significant framework distortion (i.e., breathing) upon solvent removal. Rigidification of MOFs that are built from elongated tetracarboxylate bridging ligands by unusual interlocking and interpenetration leads to highly porous and robust hybrid materials.

magnified image
Dual‐Function Probe to Detect Protease Activity for Fluorescence Measurement and 19F MRI
Authors: Mizukami Shin , Takikawa Rika , Sugihara Fuminori , Shirakawa Masahiro , Kikuchi Kazuya
Published: April 2009

Dynamic duo: Magnetic resonance imaging (MRI) can visualize deep regions of living bodies, whereas fluorescence measurement offers excellent sensitivity. These methods thus offer signal enhancement potential for detecting enzyme activities. A dual‐mode off/on probe to detect caspase‐3 activity by fluorescence and 19F MRI is presented.

magnified image
Iridium Catalysis for CH Bond Arylation of Heteroarenes with Iodoarenes
Authors: Join Benoît , Yamamoto Takuya , Itami Kenichiro
Published: April 2009

Efficient couplings using equimolar quantities of each coupling partner and multiple CH bond arylation reactions are achieved with an Ir‐based catalytic system for the CH bond arylation of electron‐rich heteroarenes with iodoarenes to construct extended π‐systems. The dramatic ligand effect on reaction efficiency leads to the discovery that Crabtree's catalyst (see scheme) is the optimal catalyst precursor.

magnified image
Formal Total Synthesis of Platencin
Authors: Varseev Georgy N. , Maier Martin E.
Published: April 2009

The right bicycle: A concise formal synthesis of platencin was based on an efficient oxygen‐mediated palladium‐catalyzed cycloalkenylation of 1 to form a bicyclo[3.2.1]octane, and a deoxygenative rearrangement of tosylhydrazone 2 to construct the bicyclo[2.2.2]octane 3. The total yield of the core structure 4 of platencin was 17.5 % for 13 steps from a commercially available compound. Ts=p‐toluenesulfonyl, TBS=tert‐butyldimethylsilyl, Piv=pivaloyl.

magnified image
Cover Picture: A Phosphorus Analogue of Bis(η4‐cyclobutadiene)iron(0) (Angew. Chem. Int. Ed. 17/2009)
Authors: Wolf Robert , Slootweg J. Chris , Ehlers Andreas W. , Hartl František , de Bruin Bas , Lutz Martin , Spek Anthony L. , Lammertsma Koop
Published: April 2009

A rare phosphorus analogue of the elusive complex bis(η4‐cyclobutadiene)iron(0) is reported by K. Lammertsma et al. in their Communication on page 3104 ff. The background of the cover picture shows John Montagu (1718–1792), 4th Earl of Sandwich and 1st Lord of the Admiralty, who certainly would not have dreamt that an important class of organometallic compounds, sandwich complexes, would bear his name one day. The synthesis of [Fe(P2C2tBu2)2] shows that sandwich complexes are still topical objects of research.

magnified image
Opinion mining and relationship discovery using CopeOpi opinion analysis system
Authors: Ku Lun‐Wei , Ho Hsiu‐Wei , Chen Hsin‐Hsi
Published: April 2009

We present CopeOpi, an opinion‐analysis system, which extracts from the Web opinions about specific targets, summarizes the polarity and strength of these opinions, and tracks opinion variations over time. Objects that yield similar opinion tendencies over a certain time period may be correlated due to the latent causal events. CopeOpi discovers relationships among objects based on their opinion‐tracking plots and collocations. Event bursts are detected from the tracking plots, and the strength of opinion relationships is determined by the coverage of these plots. To evaluate opinion mining, we use the NTCIR corpus annotated with opinion information at sentence and document levels. CopeOpi achieves sentence‐ and document‐level f‐measures of 62% and 74%. For relationship discovery, we collected 1.3M economics‐related documents from 93 Web sources over 22 months, and analyzed collocation‐based, opinion‐based, and hybrid models. We consider as correlated company pairs that demonstrate similar stock‐price variations, and selected these as the gold standard for evaluation. Results show that opinion‐based and collocation‐based models complement each other, and that integrated models perform the best. The top 25, 50, and 100 pairs discovered achieve precision rates of 1, 0.92, and 0.79, respectively.
On the Relative Preference of Enamine/Iminium Pathways in an Organocatalytic Michael Addition Reaction
Authors: Patil Mahendra P. , Sunoj Raghavan B.
Published: April 2009

The right path: The mechanism of organocatalyzed Michael addition between propanal and methyl vinyl ketone is investigated using the density functional and ab intio methods. The kinetic preference for the formation of key intermediates is established in an effort to identify the competing pathways associated with the reaction. The effect of co‐catalyst/protic solvent on the energetics of the reaction is also studied

magnified image

The mechanism of the organocatalyzed Michael addition between propanal and methyl vinyl ketone is investigated using the density functional and ab intio methods. Different modes of substrate activation offered by a secondary amine (pyrrolidine) organocatalyst are reported. The electrophilic activation of enone (P‐I) through the formation of an iminium ion, and nucleophilic activation of propanal (P‐II) in the form of enamine have been examined by identifying the corresponding transition states. The kinetic preference for the formation of key intermediates is established in an effort to identify the competing pathways associated with the title reaction. A comparison of barriers associated with different pathways as well as intermediate formation allows us to provide a suitable mechanistic rationale for Michael addition reactions catalyzed by a secondary amine. The overall barriers for the CC bond formation pathways involving enol or iminium intermediates are identified as higher than the enamine pathway. Additionally, the generation of iminium is found to be less favored as compared to enamine formation. The effect of co‐catalyst/protic solvent on the energetics of the overall reaction is also studied using the cluster continuum approach. Significant reduction in the activation energies for each step of the reaction is predicted for the solvent‐assisted models. The co‐catalyst assisted addition of propanal–enamine to methyl vinyl ketone is identified as the most preferred pathway (P‐IV) for the Michael addition reaction. The results are in concurrence with the available experimental reports on the rate acceleration by the use of a co‐catalyst in this reaction.
Functional role of Coenzyme Q in the energy coupling of NADH‐CoQ oxidoreductase (Complex I): Stabilization of the semiquinone state with the application of inside‐positive membrane potential to proteoliposomes
Authors: Ohnishi Tomoko , Ohnishi S. Tsuyoshi , Shinzawa‐Ito Kyoko , Yoshikawa Shinya
Published: April 2009

Coenzyme Q10 (which is also designated as CoQ10, ubiquinone‐10, UQ10, CoQ, UQ or simply as Q) plays an important role in energy metabolism. For NADH‐Q oxidoreductase (complex I), Ohnishi and Salerno proposed a hypothesis that the proton pump is operated by the redox‐driven conformational change of a Q‐binding protein, and that the bound form of semiquinone (SQ) serves as its gate [FEBS Letters 579 (2005) 45–55]. This was based on the following experimental results: (i) EPR signals of the fast‐relaxing SQ anion (designated as Q) are observable only in the presence of the proton electrochemical potential (Δμ); (ii) iron‐sulfur cluster N2 and Q are directly spin‐coupled; and (iii) their center‐to‐center distance was calculated as 12Å, but Q is only 5Å deeper than N2 perpendicularly to the membrane. After the priming reduction of Q to Nf, the proton pump operates only in the steps between the semiquinone anion (Q) and fully reduced quinone (QH2). Thus, by cycling twice for one NADH molecule, the pump transports 4H+ per 2e−.

This hypothesis predicts the following phenomena: (a) Coupled with the piericidin A sensitive NADH‐DBQ or Q1 reductase reaction, Δμ would be established; (b) Δμ would enhance the SQ EPR signals; and (c) the dissipation of Δμ with the addition of an uncoupler would increase the rate of NADH oxidation and decrease the SQ signals.

We reconstituted bovine heart complex I, which was prepared at Yoshikawa's laboratory, into proteoliposomes. Using this system, we succeeded in demonstrating that all of these phenomena actually took place. We believe that these results strongly support our hypothesis.
Function of a bound ubiquinone in Escherichia coli quinoprotein glucose dehydrogenase
Authors: Mustafa Golam , Ishikawa Yoshinori , Kobayashi Kazuo , Migita Catharina T. , Tagawa Seiichi , Yamada Mamoru
Published: April 2009

Membrane‐bound glucose dehydrogenase (mGDH) is a single integral protein in the respiratory chain in Escherichia coli which oxidizes D‐glucose and feeds electrons to ubiquinol oxidase via bulk ubiquinone (UQ). mGDH contains a bound UQ, CoQ8, for its intramolecular electron transfer in addition to pyrroloquinoline quinone (PQQ) as a coenzyme. Pulse radiolysis analysis revealed that the bound UQ exists very close to PQQ at a distance of 11–13 Å. Studies on mGDH mutants with substitutions for amino acid residues around PQQ showed that Asp‐466 and Lys‐493, which are crucial for catalytic activity, interact with bound UQ. Based on these findings, we propose that the bound UQ is involved in the catalytic reaction in addition to the intramolecular electron transfer in mGDH.
Effect of CoQ homologues on reactive oxygen generation by mitochondria
Authors: Imada Isuke , Sato Eisuke F. , Kira Yukimi , Inoue Masayasu
Published: April 2009

Effect of CoQ compounds (Qs) on reactive oxygen (ROS) generation by mitochondrial complex I was studied using rat liver mitochondria and chemiluminescence probe L012. Kinetic analysis revealed that short chain Qs, such as Q2 and idebenone enhanced ROS generation by mitochondrial NADH oxidase system by a succinate‐inhibitable mechanism. Lipid peroxidation in mitochondrial membranes induced by NADH and iron was inhibited by short chain Qs. The inhibitory activity was enhanced by co‐oxidation of succinate as determined by chemiluminescence method and by electron spin resonance spectroscopy. These results suggested that the reduced form of short chain Qs inhibited mitochondrial ROS generation and lipid peroxidation.
Comparison between the free‐radical‐scavenging activities with vitamin E and ubiquinol in biological systems based on their reaction rates: A research account
Authors: Mukai Kazuo , Tokunaga Aiko , Itoh Shingo , Kanesaki Yu , Ouchi Aya , Ohara Keishi , Nagaoka Shin‐ichi , Abe Kouichi
Published: April 2009

Detailed kinetic studies have been performed for the reaction of aroxyl (ArO•) radical with vitamin E (α‐, β‐, γ‐, δ‐tocopherol, TocH), ubiquinol‐10, and related antioxidants in micellar solution, using a stopped‐flow spectrophotometer. The second‐order reaction rates (κs) obtained increased in the order of hydroquinone<tocol< δ‐TocH<ubiquinol‐0< γ‐TocH∼ β‐TocH<ubiquinol‐10< α‐TocH at pH 4 ∼ 8. The antioxidants which have lower oxidation potentials (Eρ ) showed higher reactivities. The reaction rates obtained in micellar solution were pH dependent because of the dissociation of OH groups in the antioxidants. For instance, by comparing the κs values with the mole fraction of each molecular form of ubiquinol‐10, the reaction rate κs1 (1.21×105 M−1 s−1 ) for undissociated form, κs2 (1.04 × 106 M−1 s−1 ) for monoanion and κs3 (0 M−1 s−1 ) for dianion, and the pKa1 and pKa2 values (11.4 and 12.7) were determined. It was found that the relative ratio of κs values (100:21:20:2.9) of α‐, β‐, γ‐, δ‐tocopherols in micellar dispersion has good correlation with the relative biological activities for rat fetal resorption, rat haemolysis, and chicken muscle dystrophy. The relative antioxidant activities of α‐tocopherol and ubiquinol‐10 have been discussed on the basis of the products of the κs values and their concentrations in serum and several tissues (heart, muscle, liver, kidney, and brain).
NADPH‐dependent coenzyme Q reductase is the main enzyme responsible for the reduction of non‐mitochondrial CoQ in cells
Authors: Takahashi Takayuki , Okuno Masaaki , Okamoto Tadashi , Kishi Takeo
Published: April 2009

We purified an NADPH‐dependent coenzyme Q reductase (NADPH‐CoQ reductase) in rat liver cytosol and compared its enzymatic properties with those of the other CoQ10 reductases such as NADPH: quinone acceptor oxidoreductase 1 (NQO1), lipoamide dehydrogenase, thioredoxine reductase and glutathione reductase. NADPH‐CoQ reductase was the only enzyme that preferred NADPH to NADH as an electron donor and was also different from the other CoQ10 reductases in the sensitivities to its inhibitors and stimulators. Especially, Zn2+ was the most powerful inhibitor for NADPH‐CoQ reductase, but CoQ10 reduction by the other CoQ10 reductases could not be inhibited by Zn2+. Furthermore, the reduction of the CoQ9 incorporated into HeLa cells was also inhibited by Zn2+ in the presence of pyrithione, a zinc ionophore. Moreover, NQO1 gene silencing in HeLa cells by transfection of a small interfering RNA resulted in lowering of both the NQO1 protein level and the NQO1 activity by about 75%. However, this transfection did not affect the NADPH‐CoQ reductase activity and the reduction of CoQ9 incorporated into the cells. These results suggest that the NADPH‐CoQ reductase located in cytosol may be the main enzyme responsible for the reduction of non‐mitochondrial CoQ in cells.
High production of sulfide in coenzyme Q deficient fission yeast
Authors: Zhang Mei , Wakitani Shusoh , Hayashi Kazuhiro , Miki Risa , Kawamukai Makoto
Published: April 2009

We have constructed coenzyme Q deficient fission yeast strains by deletion of ten different genes, all of which are absolutely required for the CoQ10 biosynthesis. We found that sulfide was highly accumulated in all fission yeast CoQ10 deficient mutants. In fission yeast sulfide is required for the synthesis of cysteine and homocysteine which are catalyzed by cysteine synthase (Cys1a) and homocysteine synthase (Met17), respectively. To better understand the relation between sulfide metabolism and coenzyme Q, we expressed cys1a, met17 and hmt2, which encodes sulfide‐quinone oxidoreductase, in CoQ10 deficient mutants and other mutants, and measured the level of sulfide. Although expression of cys1a and met17 lowered sulfide production in CoQ10 deficient mutants, hmt2 did not lower the level of sulfide, because Hmt2 requires coenzyme Q for its function. In contrast, expression of hmt2 lowered sulfide production in cys1a and met17 mutants. These and other results indicate that coenzyme Q is important for sulfide oxidation through sulfide‐quinone oxidoreductase to detoxify excess sulfide in fission yeast.
Stimulation of coenzyme Q synthesis
Authors: Bentinger Magnus , Tekle Michael , Brismar Kerstin , Chojnacki Tadeusz , Swiezewska Ewa , Dallner Gustav
Published: April 2009

Uptake of dietary coenzyme Q (CoQ) into organs is limited but there are some exceptions such as adrenal glands and ovaries. Under deficient conditions an optimal solution could be stimulation of the endogenous synthesis. In rodent exercise, cold exposure and a few substances elevate the CoQ levels to some extent. Investigations of the nuclear receptors PPARα, RXRα and LXRα&β did not answer the question which nuclear receptor regulates CoQ biosynthesis and at present we cannot design a ligand for upregulation of the synthesis. Upon ultraviolet irradiation of CoQ a number of products are formed which influence the synthesis of the mevalonate pathway lipids. Among them epoxidated derivatives were identified. Upon chemical epoxidation of a series of polyisoprenoids it was found that none of the tested poly‐cis polyisoprenols had any effect but some of the all‐trans polyisoprenols stimulated CoQ synthesis and in some cases also inhibited cholesterol biosynthesis. Tocotrienol epoxides were proved to be very efficient, those having one epoxide in the side chain doubled or trebled the CoQ synthesis while those with two epoxides additionally also inhibited cholesterol synthesis by 50–90%. The elevation of CoQ synthesis was elicited by increased mRNA levels for biosynthetic enzymes while the inhibition point in the cholesterol synthesis was localized to oxidosqualene cyclase.
Human CoQ10 deficiencies
Authors: Quinzii C. M. , López L. C. , Naini A. , DiMauro S. , Hirano M.
Published: April 2009

Coenzyme Q10 (CoQ10 or ubiquinone) is a lipid‐soluble component of virtually all cell membranes and has multiple metabolic functions. A major function of CoQ10 is to transport electrons from complexes I and II to complex III in the respiratory chain which resides in the mitochondrial inner membrane. Deficiencies of CoQ10 (MIM 607426) have been associated with four major clinical phenotypes: 1) encephalomyopathy characterized by a triad of recurrent myoglobinuria, brain involvement, and ragged‐red fibers; 2) infantile multisystemic disease typically with prominent nephropathy and encephalopathy; 3) cerebellar ataxia with marked cerebellar atrophy; and 4) pure myopathy. Primary CoQ10 deficiencies due to mutations in ubiquinone biosynthetic genes (COQ2, PDSS1, PDSS2, and ADCK3 [CABC1]) have been identified in patients with the infantile multisystemic and cerebellar ataxic phenotypes. In contrast, secondary CoQ10 deficiencies, due to mutations in genes not directly related to ubiquinone biosynthesis (APTX, ETFDH, and BRAF), have been identified in patients with cerebellar ataxia, pure myopathy, and cardiofaciocutaneous syndrome. In many patients with CoQ10 deficiencies, the causative molecular genetic defects remain unknown; therefore, it is likely that mutations in additional genes will be identified as causes of CoQ10 deficiencies.
Positive inotropic effect of coenzyme Q10, omega‐3 fatty acids and propionyl‐L‐carnitine on papillary muscle force‐frequency responses of BIO TO‐2 cardiomyopathic Syrian hamsters
Authors: Vargiu Romina , Littarru Gian Paolo , Faa Gavino , Mancinelli Rino
Published: April 2009

The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF).

Force‐frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO‐2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega‐3 fatty acids, propionyl‐L‐carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO‐2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force‐frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607‐treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1–4 Hz). In the range of frequency of 1–4 Hz also CoQ10 and omega‐3 significantly(p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+T') and peak rate of tension fall (−T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega‐3 and PLC‐treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega‐3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects.
Coenzyme Q10 (CoQ10) in isolated diastolic heart failure in hypertrophic cardiomyopathy (HCM)
Authors: Adarsh K. , Kaur H. , Mohan V.
Published: April 2009

It is well known that by improving mitochondrial bioenergetics, Coenzyme Q10 improves the systolic function in heart failure. The aim of this study was to see whether it benefits the diastolic dysfunction in hypertrophic cardiomyopathy (HCM) cases since diastolic relaxation also requires energy like the systole. 200 mg/day of CoQ10 was added to the conventional treatment in 46 patients with HCM diagnosed clinically and by echocardiography and by excluding cases of long standing hypertension. A comparable group of 41 age/sex matched cases received only conventional therapy. There was a significant improvement in the parameters like NYHA class ≥ 1, in quality of life (QOL) on 6 minutes walk test, in diastolic dysfunction by ≥1 parameter and in MR ≥ 1 grade. Post treatment echocardiogram showed significant reduction in left ventricular outflow tract ( LVOT) gradient ≥15 mm Hg in obstructive cases (12 out of 46) in the treatment group. The mean interventricular septal thickness (IVS) showed a 22.4% reduction (p < 0.005). The mean posterior wall thickness showed a 23.1% reduction (p < 0.005). No patient in the treatment Group had ventricular tachycardia (VT) whereas 4 cases in the control group had VT. In both groups 1 patient was lost due to sudden cardiac death (SCD).
Coenzyme Q10 and oxidative imbalance in Down syndrome: Biochemical and clinical aspects
Authors: Tiano L. , Padella L. , Carnevali P. , Gabrielli O. , Bruge F. , Principi F. , Littarru G. P.
Published: April 2009

Down syndrome (DS) is a chromosomal abnormality (trisomy 21) associated with mental retardation and Alzheimer like dementia, characteristic change of the individual's phenotype and premature ageing. Oxidative stress is known to play a major role in this pathology since a gene dose effect leads to elevated ratio of superoxide dismutase to catalase/glutathione peroxidase compared to controls in all age categories suggesting that oxidative imbalance contributes to the clinical manifestation of DS. Hyperuricemia is another feature of DS that has an interesting relationship with oxidative stress since uric acid represents an important free radical scavenger. However its formation is connected to the conversion of Xanthine dehydrogenase (XDH) to Xanthine oxidase (XO) which leads to concomitant production of free radicals. Here we report that plasma samples from DS patients in pediatric age, despite an increased total antioxidant capacity, largely due to elevated Uric acid content (UA), present significantly elevated markers of oxidative damage such as increased allantoin levels. Moreover DS plasma samples do not differ from healthy control ones in terms of Coenzyme Q10 and susceptibility to peroxidative stimuli. On the contrary, lymphocyte and platelet CoQ10 content was significantly lower in DS patients, a fact that might underlie oxidative imbalance at a cellular level.
Diet supplement CoQ10 delays brain atrophy in aged transgenic mice with mutations in the amyloid precursor protein: An in vivo volume MRI study
Authors: Li Geng , Jack Clifford R. , Yang Xi‐Fei , Yang Edward S.
Published: April 2009

We tested the hypotheses that supplemental intake of the diet supplement Coenzyme Q10 (CoQ10) could delay brain atrophy in double transgenic amyloid precursor protein (APP) / presenilin 1 (PS1), single transgenic APP and PS1 as well as wild type mice by volume MR image in vivo. One hundred and twelve mice (28 APP/PS1, 28 APP, 28 PS1 and 28 wild types) were studied. Half of each genotype group (n = 14 per group) was treated with CoQ10 2400 mg/kg/day, and the other half with placebo for 60 days. Magnetic resonance (MR) images were used to obtain the volumes of the hemispheres and hippocampi. APP / PS1, APP, PS1 and wild type mice treated with CoQ10 exhibited significantly less atrophy in hemisphere and hippocampus than those receiving placebo. The neuro‐protective effect of the CoQ10 on hemispheric volume, and hippocampal volume was related to genotype; greater in APP/PS1 than APP and PS1 mice and less in wild type mice. Our result indicated that CoQ10 may have therapeutic potential in the prevention and treatment of MCI and AD.
Functions of coenzyme Q10 in inflammation and gene expression
Authors: Schmelzer Constance , Lindner Inka , Rimbach Gerald , Niklowitz Petra , Menke Thomas , Döring Frank
Published: April 2009

Clinical studies demonstrated the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic in cardiovascular diseases, mitochondrial myopathies and neurodegenerative diseases. More recently, expression profiling revealed that Coenzyme Q10 (CoQ10) influences the expression of several hundred genes. To unravel the functional connections of these genes, we performed a text mining approach using the Genomatix BiblioSphere. We identified signalling pathways of G‐protein coupled receptors, JAK/STAT, and Integrin which contain a number of CoQ10 sensitive genes. Further analysis suggested that IL5, thrombin, vitronectin, vitronectin receptor, and C‐reactive protein are regulated by CoQ10 via the transcription factor NFκB1. To test this hypothesis, we studied the effect of CoQ10 on the NFκB1‐dependent pro‐inflammatory cytokine TNF‐α. As a model, we utilized the murine macrophage cell lines RAW264.7 transfected with human apolipoprotein E3 (apoE3, control) or pro‐inflammatory apoE4. In the presence of 2.5 μM or 75 μM CoQ10 the LPS‐induced TNF‐α response was significantly reduced to 73.3±2.8% and 74.7±8.9% in apoE3 or apoE4 cells, respectively. Therefore, the in silico analysis as well as the cell culture experiments suggested that CoQ10 exerts anti‐inflammatory properties via NFκB1‐dependent gene expression.
Coenzyme Q10 levels in women with preeclampsia living at different altitudes
Authors: Teran Enrique , Chedraui Peter , Racines‐Orbe Marcia , Vivero Sandra , Villena Francisco , Duchicela Fabian , Nacevilla Luis , Schwager Gino , Calle Andres
Published: April 2009

Background: Preeclampsia is a common disorder of pregnancy exhibiting abnormal plasma and placental coenzyme Q10 (CoQ10) levels when compared to normal pregnancies.

Objective: To evaluate CoQ10 levels both in plasma and placenta among normal pregnant (n = 60) and preeclamptic (n = 63) primigravid women and determine the effect of high or low altitude residency.

Study design: CoQ10 was determined using High Performance Liquid Chromatography (HPLC) technique and group comparisons were performed.

Results: Preeclamptic women living at high altitude displayed significantly lower CoQ10 plasma levels (0.64±0.23 vs. 0.82±0.46 μmol/L, p = 0.05). No differences were found in CoQ10 plasma levels among women living at sea level. Interestingly, plasma CoQ10 levels at low altitude in normal pregnancies were significantly lower than high altitude normal pregnancies. Compared to normal pregnancies, preeclamptic women displayed higher placental CoQ10 content, which was only significant among those living at sea level (0.120±0.07 vs. 0.076±0.04 ng/mg protein, p < 0.005). Normal pregnant women living at high altitude displayed higher placental CoQ10 content when compared to those residing at sea level (p < 0.0005).

Conclusion: Women suffering from preeclampsia (high or low altitude) display high placental CoQ10 content, with significant low plasma CoQ10 levels among those residing in high altitude. More research is warranted to establish the cause‐effect relationship between CoQ10 levels and preeclampsia.
Plasma and thrombocyte levels of coenzyme Q10 in children with Smith‐Lemli‐Opitz syndrome (SLOS) and the influence of HMG‐CoA reductase inhibitors
Authors: Haas Dorothea , Niklowitz Petra , Hoffmann Georg F. , Andler Werner , Menke Thomas
Published: April 2009

Introduction: SLOS is caused by a defect of cholesterol synthesis. HMG‐CoA reductase inhibitors have been shown to improve biochemical parameters in this condition, but they have also been associated with CoQ10 deficiency in patients with hypercholesterolemia. The aim of this study was to analyse plasma and intracellular CoQ10 levels in SLOS patients and to determine the influence of HMG‐CoA reductase inhibitors.

Methods: Plasma concentrations of CoQ10 and vitamin E were measured in 14 patients, intracellular CoQ10 levels were determined in platelets of 10 patients with SLOS and compared to controls.

Results: Plasma CoQ10 and vitamin E levels were significantly lower in SLOS patients. This difference equalised after adjustment to cholesterol concentrations. Treatment with simvastatin did not influence CoQ10 levels and redox status. Platelet CoQ10 concentrations were similar between patients and controls but there were striking differences in the CoQ10 redox status with a decrease of oxidised CoQ10.

Conclusion: Decreased concentrations of plasma CoQ10 and vitamin E in SLOS patients are due to a diminished carrier capacity. The higher percentage of reduced CoQ10 in platelets points to an up‐regulation of mitochondrial protection mechanisms. Further studies are needed to evaluate a possible benefit of CoQ10 supplementation in SLOS patients.
Safety assessment of coenzyme Q10 (CoQ10)
Authors: Hidaka Takayoshi , Fujii Kenji , Funahashi Iwao , Fukutomi Naoki , Hosoe Kazunori
Published: April 2009

Coenzyme Q10 (CoQ10) is a naturally occurring component present in living cells. Its physiological function is to act as an essential cofactor for ATP production, and to perform important antioxidant activities in the body. In most countries, CoQ10 has been widely used as a dietary supplement for more than 20 years. Recently, the use of CoQ10 as a dietary supplement has grown with a corresponding increase in daily dosage.

The present review describes the safety profile of CoQ10 on the basis of animal and human data. The published reports concerning safety studies indicate that CoQ10 has low toxicity and does not induce serious adverse effects in humans. The acceptable daily intake (ADI) is 12mg/kg/day, calculated from the no‐observed‐adverse‐effect level (NOAEL) of 1200 mg/kg/day derived from a 52‐week chronic toxicity study in rats, i.e., 720 mg/day for a person weighing 60 kg. Risk assessment for CoQ10 based on various clinical trial data indicates that the observed safety level (OSL) for CoQ10 is 1200 mg/day/person. Evidence from pharmacokinetic studies suggest that exogenous CoQ10 does not influence the biosynthesis of endogenous CoQ9/CoQ10 nor does it accumulate into plasma or tissues after cessation of supplementation. Overall, these data from preclinical and clinical studies indicate that CoQ10 is highly safe for use as a dietary supplement. Additionally, analysis of CoQ10 bioavailability or its pharmacokinetics provides the pertinent safety evaluation for CoQ10.